Therapeutic agents comprising elastin-like peptides

ABSTRACT

The present invention provides therapeutic agents and compositions comprising elastin-like peptides (ELPs) and therapeutic proteins. In some embodiments, the therapeutic protein is a GLP-1 receptor agonist, insulin, or Factor VII/VIIa, including functional analogs. The present invention further provides encoding polynucleotides, as well as methods of making and using the therapeutic agents. The therapeutic agents have improvements in relation to their use as therapeutics, including, inter alia, one or more of half-life, clearance and/or persistance in the body, solubility, and bioavailability.

PRIORITY

This application is a continuation of U.S. application Ser. No. 16/720,970, filed Dec. 19, 2019 which is a continuation of U.S. application Ser. No. 16/000,300, filed Jun. 5, 2018, now U.S. Pat. No. 10,596,230, issued Mar. 24, 2020 which is a continuation of U.S. Ser. No. 15/816,018, filed Nov. 17, 2017, now abandoned, which is a continuation of U.S. application Ser. No. 14/822,512, filed Aug. 10, 2015, now U.S. Pat. No. 9,821,036, issued Nov. 21, 2017 which is a continuation of U.S. application Ser. No. 13/524,812, filed Jun. 15, 2012, now U.S. Pat. No. 9,127,047, issued Sep. 8, 2015 which is a continuation of U.S. application Ser. No. 13/445,979, filed Apr. 13, 2012, now U.S. Pat. No. 9,200,083, issued Dec. 1, 2015 which is a continuation of U.S. application Ser. No. 12/493,912, filed Jun. 29, 2009, now U.S. Pat. No. 8,178,495, issued May 15, 2012, which claims priority to U.S. Provisional Application No. 61/076,221, filed Jun. 27, 2008, the contents of each of which are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

This application discloses therapeutic agents comprising elastin-like-peptides, and is related to PCT/US2007/077767 (published as WO 2008/030968 on Mar. 13, 2008) having an International Filing Date of Sep. 6, 2007. This application is also related to PCT/US2006/048572 (published as WO 2007/073486 on Jun. 28, 2007) having an International Filing Date of Dec. 20, 2006. WO 2008/030968 and WO 2007/073486 are each hereby incorporated by reference in their entireties.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename:PHAS-010_10US_SeqList_ST25.txt, date recorded: Aug. 27, 2021, file size 52.7 kb).

BACKGROUND OF THE INVENTION

Therapeutic proteins or peptides in their native state or when recombinantly produced can be labile molecules exhibiting, inter alia, short periods of serum stability, serum half-life (i.e., circulatory half-life), or limited persistance in the body. Such molecules can also be extremely labile when formulated, such as when formulated in aqueous solutions.

In some instances, polyethylene glycol (PEG) conjugated to a proteinaceous molecule results in a longer-acting, sustained activity of the molecule. PEG attachment, however, can often substantially reduce or even destroy the protein's therapeutic activity. Therapeutic proteins and/or peptides have also been stabilized by fusion to certain proteins that are capable of extending serum half-life. For example, in some instances, therapeutic proteins fused to albumin, transferrin, and antibody fragments exhibit extended serum half-life when compared to the therapeutic protein in the unfused state. See U.S. Pat. No. 7,238,667 (particularly with respect to albumin conjugates), U.S. Pat. No. 7,176,278 (particularly with respect to transferrin conjugates), and U.S. Pat. No. 5,766,883, which are each hereby incorporated by reference in their entireties.

There remains a need in the art for more stable, longer acting, and/or effective proteinaceous molecules.

SUMMARY OF THE INVENTION

The present invention provides therapeutic agents comprising an elastin-like peptide (ELP) component and a therapeutic proteinacious component. The ELP component contains structural peptide units, which may be repeating units, structurally related to, or derived from, sequences of the elastin protein. Such ELP components provide certain therapeutic advantages to the therapeutic agent, such as comparatively better stability, solubility, bioavailability, half-life, persistance, and/or biological action of the therapeutic proteinaceous component. Such properties may be determined, for example, with respect to the therapeutic component's unfused or unconjugated counterpart. In some embodiments, the ELP components may undergo a reversible inverse phase transition, which may impart additional practical and/or therapeutic advantages. The invention further provides polynucleotides encoding the therapeutic agents of the invention, as well as methods of treatment or prophylaxis for certain biological conditions.

In a first aspect, the invention provides a therapeutic agent comprising an elastin-like peptide (ELP) component and a therapeutic proteinacious component, as well as pharmaceutical compositions containing the same for delivery to a subject or patient in need. The therapeutic component may be selected from active portions of the therapeutic proteins listed in Table 1, or functional analogs thereof. In certain embodiments, the therapeutic component is a GLP-1 receptor agonist, such as GLP-1, exendin-4, or a functional analog thereof. Such therapeutic components are generally effective for, among other things, increasing insulin secretion from the pancreas in a glucose-dependent manner. In other embodiments, the therapeutic component is an insulin or functional analog thereof, which is generally effective for promoting glucose uptake from the blood and storage within cells. In still other embodiments, the therapeutic component is a Factor VII/VIIa or functional analog thereof, which is generally effective for promoting coagulation by activation of Factor X or Factor IX.

The ELP and therapeutic components may be covalently coupled by various means, including chemical coupling (e.g., conjugation) and recombinant fusion technology. In addition, the number of ELP or therapeutic components per molecule, and their respective positions within the molecule, may vary as needed. The therapeutic agent may further include one or more spacer or linker moieties, which in addition to providing the desired functional independence of the ELP and therapeutic components, may optionally provide for additional functionalities, such as a protease-sensitive feature to allow for proteolytic release or activation of the therapeutic component. The therapeutic agent may further include one or more targeting components such as, for example, a peptide or protein to target the therapeutic agent to a particular cell type, e.g., a cancer cell, or to a particular organ.

In a second aspect, the invention provides polynucleotides, such polynucleotides comprising a nucleotide sequence encoding a therapeutic agent of the invention. For example, the nucleotide sequence encodes an ELP fusion with a functional portion of at least one therapeutic protein listed in Table 1 (or functional analog thereof). In certain embodiments, the therapeutic component is a GLP-1 receptor agonist (including GLP-1 and exendin-4), insulin, Factor VII/VIIa, or functional analog thereof. Such polynucleotides may further comprise additional control element(s) operably linked to the nucleotide sequence, such as promoter elements and/or other transcription or expression-related signals. The polynucleotide may be inserted into various vectors, which may be useful for production of the therapeutic agent in host cells, including, for example, bacterial and eukaryotic host cells.

In a third aspect, the invention provides a method for treating or preventing a disease, disorder, or condition in a subject, such as in a mammalian patient, including a human patient. The method comprises administering an effective amount of the therapeutic agent of the invention (or pharmaceutical composition containing the same) to a subject or patient in need thereof. For example, the patient may be in need of an agent having a biological activity or preferred indication listed in Table 1. In certain embodiments employing a GLP-1 receptor agonist/ELP compound or employing an insulin/ELP compound, the invention provides a method for treating one or more disorders including type 1 or type 2 diabetes, hyperglycemia, and impaired glucose tolerance. In certain other embodiments employing Factor VII/VIIa/ELP compound, the invention provides a method for treating one or more disorders including hemophilia, post-surgical bleeding, anticoagulation-induced bleeding, thrombocytopenia, factor VII deficiency, factor XI deficiency, and intracranial hemorrhage.

Various other aspects, features and embodiments of the invention will be more fully apparent from the following disclosure and appended claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts plasmid pET24d-ELP1-90, encoding an ELP component with a 10 unit VPGXG (SEQ ID NO: 3) repeat motif, where guest position X is V, G, and A in the ratio of 5:3:2. This motif is repeated eight times with a final C-terminal 10-unit repeat where X is V, G, A, and W in the ratio 4:3:2:1. This ELP component is represented generally as [(VPGXG)₁₀]₉.

FIG. 2A depicts plasmid pET24d-Ex-4 ELP1-90 encoding an ELP component with VPGXG (SEQ ID NO: 3) repeat motif (as in FIG. 1 ) cloned in frame with an N-terminal exendin-4 component. FIG. 2B depicts the nucleotide and amino acid sequence of the exendin-4/ELP fusion (SEQ ID NOS: 23 and 24). Primer sequences are indicated (SEQ ID NOS:35-40).

FIG. 3A depicts the nucleotide and amino acid sequence of an exendin-4 construct having an N-terminal Tev (Tobacco Etch Virus cysteine protease) cleavage site (SEQ ID NOS: 25 and 26). Primer sequences are indicated (SEQ ID NOS:38, 41, 42). FIG. 3B also depicts the nucleotide and amino acid sequence of an exendin-4 construct having an N-terminal Tev cleavage site, but with an additional sequence N-terminal to the Tev cleavage site to provide a better target for the protease (SEQ ID NOS: 27 and 28). Primer sequences are indicated (SEQ ID NOS:38, 43,44).

FIG. 4A depicts the nucleotide and amino acid sequence of an exendin-4/ELP fusion as in FIGS. 1-3 , but with a DsbA leader sequence to direct secretion into the periplasmic space (SEQ ID NOS: 29 and 30). Primer sequences are indicated (SEQ ID NOS:38, 45, 46). FIG. 4B depicts plasmid pET24d-DsbA-Ex-4 ELP1-90 encoding the fusion of FIG. 4A.

FIG. 5A depicts pPB0868, which encodes GLP-1(A8G,7-37)ELP1-90.

FIG. 5B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 53 and 54, respectively).

FIG. 6A depicts pPB1022, which encodes GLP-1(A8G,7-37)ELP1-120.

FIG. 6B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 55 and 56, respectively).

FIG. 7A depicts pPB0788, which encodes Factor VII-ELP1-90. FIG. 7B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 57 and 58, respectively).

FIG. 8A depicts the nucleotide and amino acid sequence of an insulin (B, C, and A chains) having the ELP component cloned in frame (SEQ ID NOS: 31 and 32). Primer sequences are indicated (SEQ ID NOS: 47 and 48). FIG. 8B depicts plasmid pET24d Insulin-ELP1-90 expressing the insulin/ELP fusion of FIG. 8A.

FIG. 9 is a Western blot for FVII-ELP1-90 from transient transfection of Freestyle HEK293, detected with mouse anti-human FVII monoclonal antibody. Lanes are: (1) culture media; (2) FVII ELP1-90 after purification by phase transition; and FVII control.

FIG. 10 is an SDS-PAGE showing recombinant production of an Exendin-4/ELP4-60 fusion. Lanes are: (M) Protein markers; (1) Exendin-4 ELP4-60 from total lysate; (2) Exendin-4 ELP4-60 from insoluble lysate; (3) Exendin-4 ELP4-60 from soluble lysate; (4) Exendin-4 ELP4-60 from 1st transition (equal volume); (5) Exendin-4 ELP4-60 from 2nd transition (concentrated); (6) Exendin-4 ELP4-60 from 3rd transition (concentrated).

FIG. 11 shows the activation of Factor X by FactorVIIa-ELP1-90, and by Factor VIIa as a comparison. As shown, FactorVIIa-ELP retains full activity.

FIG. 12 shows that Factor VIIa-ELP1-90 has a long PK when administered by i.v. in rats. FactorVIIa has a T_(1/2) of about 690 min. as compared to about 45-60 min. for Factor VIIa.

FIG. 13 shows the high in vitro activity of GLP1-ELP and Exendin-4-ELP, when compared to the activity of Exendin peptide.

FIG. 14 shows that GLP1-ELP has a T_(1/2), of about 12.9 hours when administered by i.v. to rats, and a T_(1/2), of about 8.6 hours when administered subcutaneously (SQ).

FIG. 15 shows that GLP-1 ELP has a long half-life in rabbits of about 20 hours when administered i.v., and about 24 hours when administered sub-cutaneously.

FIG. 16 shows sustained glycemic control in diabetic mice with GLP-1-ELP.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides therapeutic agents comprising an elastin-like peptide (ELP) (“the ELP component”) and a therapeutic component. The therapeutic component may be selected from Table 1 (e.g., selected from a Therapeutic Protein, or functional portion or functional analog thereof, listed in Table 1). In certain embodiments, the therapeutic component is a GLP-1 receptor agonist, such as GLP-1 or exendin-4, or may be insulin, Factor VII/VIIa, or functional analog thereof. The ELP component contains structural units related to, or derived from, sequences of the elastin protein, which provides certain therapeutic advantages, such as comparatively better persistence, stability, solubility, bioavailability, half-life, and/or biological action of the therapeutic component. Such properties may be determined with respect to, for example, an unfused or unconjugated counterpart of the therapeutic component. The invention further provides polynucleotides encoding the therapeutic agents of the invention, as well as methods of treatment or prophylaxis for certain biological conditions, including the preferred indications listed in Table 1, and including diabetes (e.g., Type I and Type II), hyperglycemia, bleeding, hemophilia, and hemorrhage, among others.

For ease of reference in the ensuing discussion, set out below are definitions of some terms appearing in the discussion.

As used herein, the term “therapeutic agent” or “therapeutic component” refers to an agent or component capable of inducing a biological effect in vivo and/or in vitro. The biological effect may be useful for treating and/or preventing a condition, disorder, or disease in a subject or patient.

As used herein, the term “coupled” means that the specified components are either directly covalently bonded to one another (e.g., via chemical conjugation or recombinant fusion technology), or indirectly covalently joined to one another (e.g., via chemical conjugation or recombinant fusion technology) through an intervening moiety or moieties, such as a bridge, spacer, or linker.

As used herein, “half-life” (which generally refers to in vivo half-life or circulatory half-life) is the period of time that is required for a 50% diminution of bioactivity of the active agent to occur. Such term is to be contrasted with “persistence,” which is the overall temporal duration of the active agent in the body, and “rate of clearance” as being a dynamically changing variable that may or may not be correlative with the numerical values of half-life and persistence.

The term “functional analog” refers to a protein that is an active analog (e.g., either chemical or protein analog), derivative, fragment, truncation isoform or the like of a native protein. For example, the functional analog may be a functional analog of a therapeutic protein listed in Table 1, or may be a functional analog of a GLP-1 receptor agonist (e.g., GLP-1, exendin), insulin, or Factor VII/VIIa. A polypeptide is active when it retains some or all of the biological activity of the corresponding native polypeptide, as determined in vivo or in one or more indicative in vitro assays. Exemplary activity assays for certain therapeutic proteins, which are determinative of activity, are listed Table 1. Further, such biological activities and assays for GLP-1 receptor agonists, insulin, and Factor VII/VIIa, which are determinative of whether a given molecule is a “functional analog,” are described in detail elsewhere herein.

As used herein, the term “native,” as used in reference to an amino acid sequence, indicates that the amino acid sequence is found in a naturally-occurring protein.

As used herein, the term “spacer” refers to any moiety, peptide or other chemical entity, that may be interposed between the ELP component and the therapeutic component. For example, the spacer may be a divalent group that is covalently bonded at one terminus to the ELP component, and covalently bonded at the other terminus to the therapeutic component. The therapeutic agents may therefore be open to the inclusion of additional chemical structure that does not preclude the efficacy of the agent for its intended purpose. The spacer may, for example, be a protease-sensitive spacer moiety that is provided to control the pharmacokinetics of the agent, or the spacer may be a protease-resistant moiety.

The therapeutic component and the ELP component may be coupled with one another in any suitable covalent manner, including chemical coupling and recombinant technology, such that the therapeutic agent is efficacious for its intended purpose, and such that the presence of the ELP component enhances the therapeutic component in some functional, therapeutic or physiological aspect. For example, the ELP-coupled therapeutic component may be enhanced in, e.g., its bioavailability, bio-unavailability, therapeutically effective dose, biological action, formulation compatibility, resistance to proteolysis or other degradative modality, solubility, half-life or other measure of persistence in the body subsequent to administration, rate of clearance from the body subsequent to administration, etc. Such enhancement may be determined, for example, in relation to a corresponding unconjugated or unfused counterpart therapeutic (e.g., determined relative to native GLP-1, exendin, insulin, or Factor VII/VIIa, or a therapeutic protein listed in Table 1).

In some embodiments, the therapeutic agent of the invention circulates or exists in the body in a soluble form, and escapes filtration by the kidney thereby persisting in the body in an active form. In some embodiments, the therapeutic agents of the invention have a molecular weight of less than the generally recognized cut-off for filtration through the kidney, such as less than about 60 kD, or in some embodiments less than about 55, 50, 45, 40, 30, or 20 kDa, and persist in the body by at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 100-fold longer than an uncoupled (e.g., unfused or unconjugated) therapeutic counterpart.

The number of ELP and/or therapeutic components per molecule, and their respective positions within the molecule, may vary among embodiments of the invention. For example, in embodiments where the agent is a recombinant fusion, at least one ELP component may be placed at one or both of the N-terminus and the C-terminus. Where the ELP component is at both the N-terminus and C-terminus of the fusion, the ELP components will flank the therapeutic component. Alternatively, the therapeutic component may be positioned at either or both of the N-terminus and C-terminus. Where the therapeutic component is at both the N-terminus and C-terminus, the therapeutic component will flank the ELP component. In a further embodiment, different therapeutic components are positioned at the N-terminus and C-terminus of the molecule. As discussed in detail herein, in certain embodiments, such therapeutic component(s) may be released by proteolysis of a spacer moiety separating the ELP and therapeutic components. In certain embodiments, the therapeutic component may be inactive in the fused state, and becoming active upon proteolytic release from the ELP component(s). Alternatively, the therapeutic component remains active in the fused state, making proteolytic processing of the therapeutic agent unnecessary for biological activity.

When prepared as recombinant fusions, the therapeutic agent can be prepared by known recombinant expression techniques. For example, to recombinantly produce the therapeutic agent, a nucleic acid sequence encoding the chimeric gene is operatively linked to a suitable promoter sequence such that the nucleic acid sequence encoding such fusion protein will be transcribed and/or translated into the desired fusion protein in the host cells. Preferred promoters are those useful for expression in E. coli, such as the T7 promoter. Any commonly used expression system may be used, including eukaryotic or prokaryotic systems. Specific examples include yeast (e.g., Saccharomyces spp., Pichia spp.), baculovirus, mammalian, and bacterial systems, such as E. coli, and Caulobacter.

The various aspects and embodiments of the invention are described in greater detail in the following sections.

Elastin-Like Peptide (ELP) Component

The therapeutic agent of the invention may comprise one or more ELP components. The ELP components comprise or consist of structural peptide units or sequences that are related to, or derived from, the elastin protein. Such sequences are useful for improving the properties of therapeutic proteins, such as those listed in Table 1, as well as GLP-1 receptor agonists (e.g., GLP-1 or exendin-4), insulin, and Factor VII/VIIa in one or more of bioavailability, therapeutically effective dose, biological action, formulation compatibility, resistance to proteolysis, solubility, half-life or other measure of persistence in the body subsequent to administration, and/or rate of clearance from the body.

The ELP component is constructed from structural units of from three to about twenty amino acids, or in some embodiments, from four to ten amino acids, such as five or six amino acids. The length of the individual structural units, in a particular ELP component, may vary or may be uniform. In certain embodiments, the ELP component is constructed of a polytetra-, polypenta-, polyhexa-, polyhepta-, polyocta, and polynonapeptide motif of repeating structural units. Exemplary structural units include units defined by SEQ ID NOS: 1-12 (below), which may be employed as repeating structural units, including tandem-repeating units, or may be employed in some combination, to create an ELP effective for improving the properties of the therapeutic component. Thus, the ELP component may comprise or consist essentially of structural unit(s) selected from SEQ ID NOS: 1-12, as defined below.

The ELP component, comprising such structural units, may be of varying sizes. For example, the ELP component may comprise or consist essentially of from about 10 to about 500 structural units, or in certain embodiments about 15 to about 150 structural units, or in certain embodiments from about 20 to about 100 structural units, or from about 50 to about 90 structural units, including one or a combination of units defined by SEQ ID NOS: 1-12. Thus, the ELP component may have a length of from about 50 to about 2000 amino acid residues, or from about 100 to about 600 amino acid residues, or from about 200 to about 500 amino acid residues, or from about 200 to about 400 amino acid residues.

In some embodiments, the ELP component, or in some cases the therapeutic agent, has a size of less than about 65 kDa, or less than about 60 kDa, or less than about 55 kDa, or less than about 50 kDa, or less than about 40 kDa, or less than about 30 or 25 kDa. Three major blood proteins, Human Serum Albumin (HSA), Transferrin (Tf) and IgG, or the Fc portion of IgGs in their glycosylated form, have been exploited to extend the half-lives of proteins and peptides for improved therapeutic use. These molecules are 585, 679 and 480 amino acids in length giving molecular weights of about 66, 77, and ˜75 kDa (including glycosylations), respectively. They are each globular and relatively compact. The half life of these molecules is determined by a number of factors, including charge distribution, rescue of molecules by the neonatal Fc receptor (FcRn) (HSA and Fc) or cycling of Tf through the Tf receptor (TfR), and their size which prevents filtering through the kidney glomerulus. HSA is slightly below the generally regarded cut-off for filtration through the kidney (˜70 kDa) but its charge distribution helps prevent this. It would be anticipated that, in order to achieve half-life extension of the same order as that achieved with HSA, Tf and Fc, a protein of at least this molecular weight range would be required or desirable, i.e. having over 550 amino acids and being over 65 kDa. However, an ELP with a small number of amino acids relative to HSA, Tf and Fc (e.g., in the range of about 300 to 400) and around 30 to 40 kDa may have a half life that matches and/or exceeds that of HSA, Tf, and Fc.

In some embodiments, the ELP component in the untransitioned state may have an extended, relatively unstructured and non-globular form, and thus such molecules may have a large expanded structure in comparison to HSA, Tf and Fc, so as to escape kidney filtration. In such embodiments, the therapeutic agents of the invention have a molecular weight of less than the generally recognized cut-off for filtration through the kidney, such as less than about 60 kD, or in some embodiments less than about 55, 50, 45, 40, 30, or 25 kDa, and persist in the body by at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 100-fold longer than an uncoupled (e.g., unfused or unconjugated) therapeutic counterpart.

In certain embodiments, the ELP component undergoes a reversible inverse phase transition. That is, the ELP components are structurally disordered and highly soluble in water below a transition temperature (Tt), but exhibit a sharp (2-3° C. range) disorder-to-order phase transition when the temperature is raised above the Tt, leading to desolvation and aggregation of the ELP components. For example, the ELP forms insoluble polymers, when reaching sufficient size, which can be readily removed and isolated from solution by centrifugation. Such phase transition is reversible, and isolated insoluble ELPs can be completely resolubilized in buffer solution when the temperature is returned below the Tt of the ELPs. Thus, the therapeutic agents of the invention can, in some embodiments, be separated from other contaminating proteins to high purity using inverse transition cycling procedures, e.g., utilizing the temperature-dependent solubility of the therapeutic agent, or salt addition to the medium. Successive inverse phase transition cycles can be used to obtain a high degree of purity. In addition to temperature and ionic strength, other environmental variables useful for modulating the inverse transition of the therapeutic agents include pH, the addition of inorganic and organic solutes and solvents, side-chain ionization or chemical modification, and pressure.

In certain embodiments, the ELP component does not undergo a reversible inverse phase transition, or does not undergo such a transition at a biologically relevant Tt, and thus the improvements in the biological and/or physiological properties of the molecule (as described elsewhere herein), may be entirely or substantially independent of any phase transition properties. Nevertheless, such phase transition properties may impart additional practical advantages, for example, in relation to the recovery and purification of such molecules.

In certain embodiments, the ELP component(s) may be formed of structural units, including but not limited to:

-   -   (a) the tetrapeptide Val-Pro-Gly-Gly, or VPGG (SEQ ID NO: 1);     -   (b) the tetrapeptide Ile-Pro-Gly-Gly, or IPGG (SEQ ID NO: 2);     -   (c) the pentapeptide Val-Pro-Gly-X-Gly (SEQ ID NO: 3), or VPGXG,         where X is any natural or non-natural amino acid residue, and         where X optionally varies among polymeric or oligomeric repeats;     -   (d) the pentapeptide Ala-Val-Gly-Val-Pro, or AVGVP (SEQ ID NO:         4);     -   (e) the pentapeptide Ile-Pro-Gly-X-Gly, or IPGXG (SEQ ID NO: 5),         where X is any natural or non-natural amino acid residue, and         where X optionally varies among polymeric or oligomeric repeats;     -   (e) the pentapeptide Ile-Pro-Gly-Val-Gly, or IPGVG (SEQ ID NO:         6);     -   (f) the pentapeptide Leu-Pro-Gly-X-Gly, or LPGXG (SEQ ID NO: 7),         where X is any natural or non-natural amino acid residue, and         where X optionally varies among polymeric or oligomeric repeats;     -   (g) the pentapeptide Leu-Pro-Gly-Val-Gly, or LPGVG (SEQ ID NO:         8);     -   (h) the hexapeptide Val-Ala-Pro-Gly-Val-Gly, or VAPGVG (SEQ ID         NO: 9);     -   (I) the octapeptide Gly-Val-Gly-Val-Pro-Gly-Val-Gly, or GVGVPGVG         (SEQ ID NO: 10);     -   (J) the nonapeptide Val-Pro-Gly-Phe-Gly-Val-Gly-Ala-Gly, or         VPGFGVGAG (SEQ ID NO: 11); and     -   (K) the nonapeptides Val-Pro-Gly-Val-Gly-Val-Pro-Gly-Gly, or         VPGVGVPGG (SEQ ID NO: 12).         Such structural units defined by SEQ ID NOS:1-12 may form         structural repeat units, or may be used in combination to form         an ELP component in accordance with the invention. In some         embodiments, the ELP component is formed entirely (or almost         entirely) of one or a combination of (e.g., 2, 3 or 4)         structural units selected from SEQ ID NOS: 1-12. In other         embodiments, at least 75%, or at least 80%, or at least 90% of         the ELP component is formed from one or a combination of         structural units selected from SEQ ID NOS: 1-12, and which may         be present as repeating units.

In certain embodiments, the ELP component(s) contain repeat units, including tandem repeating units, of the pentapeptide Val-Pro-Gly-X-Gly (SEQ ID NO:3), where X is as defined above, and where the percentage of Val-Pro-Gly-X-Gly (SEQ ID NO:3) pentapeptide units taken with respect to the entire ELP component (which may comprise structural units other than VPGXG (SEQ ID NO:3)) is greater than about 75%, or greater than about 85%, or greater than about 95% of the ELP component. The ELP component may contain motifs having a 5 to 15-unit repeat (e.g. about 10-unit repeat) of the pentapeptide of SEQ ID NO: 3, with the guest residue X varying among at least 2 or at least 3 of the units. The guest residues may be independently selected, such as from the amino acids V, I, L, A, G, and W (and may be selected so as to retain a desired inverse phase transition property). The repeat motif itself may be repeated, for example, from about 5 to about 12 times, such as about 8 to 10 times, to create an exemplary ELP component. The ELP component as described in this paragraph may of course be constructed from any one of the structural units defined by SEQ ID NOS: 1-12, or a combination thereof.

In some embodiments, the ELP component may include a β-turn structure. Exemplary peptide sequences suitable for creating a β-turn structure are described in International Patent Application PCT/US96/05186, which is hereby incorporated by reference in its entirety. For example, the fourth residue (X) in the elastin pentapeptide sequence, VPGXG (SEQ ID NO:3), can be altered without eliminating the formation of a β-turn. Alternatively, the ELP component may lack a β-turn, or otherwise have a different conformation and/or folding character.

In certain embodiments, the ELP components include polymeric or oligomeric repeats of the pentapeptide VPGXG (SEQ ID NO: 3), where the guest residue X is any amino acid. X may be a naturally occurring or non-naturally occurring amino acid. In some embodiments, X is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine. In some embodiments, X is a natural amino acid other than proline or cysteine.

The guest residue X (e.g., with respect to SEQ ID NO: 3, or other ELP structural unit) may be a non-classical (non-genetically encoded) amino acid. Examples of non-classical amino acids include: D-isomers of the common amino acids, 2,4-diaminobutyric acid, α-amino isobutyric acid, A-aminobutyric acid, Abu, 2-amino butyric acid, γ-Abu, ε-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, omithine, norieucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenyiglycine, cyclohexylalanine, β-alanine, fluoro-amino acids, designer amino acids such as β-methyl amino acids, Cα-methyl amino acids, Nα-methyl amino acids, and amino acid analogs in general.

Selection of X is independent in each ELP structural unit (e.g., for each structural unit defined herein having a guest residue X). For example, X may be independently selected for each structural unit as an amino acid having a positively charged side chain, an amino acid having a negatively charged side chain, or an amino acid having a neutral side chain, including in some embodiments, a hydrophobic side chain.

In still other embodiments, the ELP component(s) may include polymeric or oligomeric repeats of the pentapeptides VPGXG (SEQ ID NO:3), IPGXG (SEQ ID NO:5) or LPGXG (SEQ ID NO:7), or a combination thereof, where X is as defined above.

In each embodiment, the structural units, or in some cases polymeric or oligomeric repeats, of the ELP sequences may be separated by one or more amino acid residues that do not eliminate the overall effect of the molecule, that is, in imparting certain improvements to the therapeutic component as described. In certain embodiments, such one or more amino acids also do not eliminate or substantially affect the phase transition properties of the ELP component (relative to the deletion of such one or more amino acids).

In each repeat, X is independently selected. The structure of the resulting ELP components may be described using the notation ELPk [X_(i)Y_(j)-n], where k designates a particular ELP repeat unit, the bracketed capital letters are single letter amino acid codes and their corresponding subscripts designate the relative ratio of each guest residue X in the structural units (where applicable), and n describes the total length of the ELP in number of the structural repeats. For example, ELP1 [V₅A₂G₃-10] designates an ELP component containing 10 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is valine, alanine, and glycine at a relative ratio of 5:2:3; ELP1 [K₁V₂F₁-4] designates an ELP component containing 4 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:2:1; ELP1 [K₁V₇F₁-9] designates a polypeptide containing 9 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:7:1; ELP1 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is exclusively valine; ELP1 [V-20] designates a polypeptide containing 20 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is exclusively valine; ELP2 [5] designates a polypeptide containing 5 repeating units of the pentapeptide AVGVP (SEQ ID NO:4); ELP3 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide IPGXG (SEQ ID NO:5), where X is exclusively valine; ELP4 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide LPGXG (SEQ ID NO:7), where X is exclusively valine. Such ELP components as described in this paragraph may be used in connection with the present invention to increase the therapeutic properties of the therapeutic component.

Further, the Tt is a function of the hydrophobicity of the guest residue. Thus, by varying the identity of the guest residue(s) and their mole fraction(s), ELPs can be synthesized that exhibit an inverse transition over a 0-100° C. range. Thus, the Tt at a given ELP length may be decreased by incorporating a larger fraction of hydrophobic guest residues in the ELP sequence. Examples of suitable hydrophobic guest residues include valine, leucine, isoleucine, phenyalanine, tryptophan and methionine. Tyrosine, which is moderately hydrophobic, may also be used. Conversely, the Tt may be increased by incorporating residues, such as those selected from the group consisting of: glutamic acid, cysteine, lysine, aspartate, alanine, asparagine, serine, threonine, glycine, arginine, and glutamine; preferably selected from alanine, serine, threonine and glutamic acid.

The ELP component in some embodiments is selected or designed to provide a Tt ranging from about 10 to about 80° C., such as from about 35 to about 60° C., or from about 38 to about 45° C. In some embodiments, the Tt is greater than about 40° C. or greater than about 42° C., or greater than about 45° C., or greater than about 50° C. The transition temperature, in some embodiments, is above the body temperature of the subject or patient (e.g., >37° C.) thereby remaining soluble in vivo, or in other embodiments, the Tt is below the body temperature (e.g., <37° C.) to provide alternative advantages, such as in vivo formation of a drug depot for sustained release of the therapeutic agent.

The Tt of the ELP component can be modified by varying ELP chain length, as the Tt generally increases with decreasing MW. For polypeptides having a molecular weight >100,000, the hydrophobicity scale developed by Urry et al. (PCT/US96/05186, which is hereby incorporated by reference in its entirety) is preferred for predicting the approximate Tt of a specific ELP sequence. However, in some embodiments, ELP component length can be kept relatively small, while maintaining a target Tt, by incorporating a larger fraction of hydrophobic guest residues (e.g., amino acid residues having hydrophobic side chains) in the ELP sequence. For polypeptides having a molecular weight <100,000, the Tt may be predicted or determined by the following quadratic function: Tt=M₀+M₁X+M₂X² where X is the MW of the fusion protein, and M₀=116.21; M₁=−1.7499; M₂=0.010349.

While the Tt of the ELP component, and therefore of the ELP component coupled to a therapeutic component, is affected by the identity and hydrophobicity of the guest residue, X, additional properties of the molecule may also be affected. Such properties include, but are not limited to solubility, bioavailability, persistence, and half-life of the molecule.

As described in PCT/US2007/077767 (published as WO 2008/030968), which is hereby incorporated by reference in its entirety, the ELP-coupled therapeutic component can retain the therapeutic component's biological activity. Additionally, ELPs themselves can exhibit long half-lives. Therefore, ELP components in accordance with the present invention substantially increase (e.g. by greater than 10%, 20%, 30%, 50%, 100%, 200%, 500% or more, in specific embodiments) the half-life of the therapeutic component when conjugated thereto. Such half-life (or in some embodiments persistance or rate of clearance) is determined in comparison to the half-life of the free (unconjugated or unfused) form of the therapeutic component. Furthermore, ELPs may target high blood content organs, when administered in vivo, and thus, can partition in the body, to provide a predetermined desired corporeal distribution among various organs or regions of the body, or a desired selectivity or targeting of a therapeutic agent. In sum, the therapeutic agents contemplated by the invention are administered or generated in vivo as active compositions having extended half-lives (e.g., circulatory half-life), among other potential benefits described herein.

The invention thus provides various agents for therapeutic (in vivo) application, where the therapeutic component is biologically active. Such therapeutic components include those listed in Table 1 (e.g., full length or functional portions or functional analogs thereof), as well as GLP-1 receptor agonists such as GLP-1 or exendin-4, insulin, or Factor VII/VIIa, and functional analogs thereof. The structure and activity of such therapeutic components are described in detail below. In some forms of the therapeutic agent, the coupling of the therapeutic component to the ELP component is effected by direct covalent bonding or indirect (through appropriate spacer groups) bonding (as described elsewhere herein). Further, the therapeutic component(s) and the ELP component(s) can be structurally arranged in any suitable manner involving such direct or indirect covalent bonding, relative to one another.

Glucagon-Like Peptide (GLP)-1 Receptor Agonists

In certain embodiments of the invention, the therapeutic agent comprises an ELP component fused or conjugated to a GLP-1 receptor agonist, such as GLP-1, exendin-4, or functional analogs thereof.

Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which is synthesized in the L-cells in the distal ileum, in the pancreas, and in the brain. Processing of preproglucagon to give GLP-1 (7-36)amide, GLP-1 (7-37) and GLP-2 occurs mainly in the L-cells. A simple system is used to describe fragments and analogs of this peptide. For example, Gly-GLP-1 (7-37) designates a fragment of GLP-1 formally derived from GLP-1 by deleting the amino acid residues Nos. 1 to 6 and substituting the naturally occurring amino acid residue in position 8 (Ala) by Gly. Similarly, Lys³⁴ (N^(ε)-tetradecanoyl)-GLP-1(7-37) designates GLP-1 (7-37) wherein the ε-amino group of the Lys residue in position 34 has been tetradecanoylated. Where reference in this text is made to C-terminally extended GLP-1 analogues, the amino acid residue in position 38 is Arg unless otherwise indicated, the optional amino acid residue in position 39 is also Arg unless otherwise indicated and the optional amino acid residue in position 40 is Asp unless otherwise indicated. Also, if a C-terminally extended analogue extends to position 41, 42, 43, 44 or 45, the amino acid sequence of this extension is as in the corresponding sequence in human preproglucagon unless otherwise indicated.

The parent peptide of GLP-1, proglucagon (PG), has several cleavage sites that produce various peptide products dependent on the tissue of origin including glucagon (PG[32-62]) and GLP-1[7-36]NH₂ (PG[72-107]) in the pancreas, and GLP-1[7-37] (PG[78-108]) and GLP-1[7-36]NH₂ (PG [78-107]) in the L cells of the intestine where GLP-1[7-36]NH₂ (78-107 PG) is the major product. The GLP-1 component in accordance with the invention may be any biologically active product or deivative of proglocagon, or functional analog thereof, including: GLP-1 (1-35), GLP-1(1-36), GLP-1 (1-36)amide, GLP-1 (1-37), GLP-1 (1-38), GLP-1 (1-39), GLP-1 (1-40), GLP-1 (1-41), GLP-1 (7-35), GLP-1 (7-36), GLP-1 (7-36)amide, GLP-1 (7-37), GLP-1 (7-38), GLP-1 (7-39), GLP-1 (7-40) and GLP-1 (7-41), or a analog of the foregoing. Generally, the GLP-1 component in some embodiments may be expressed as GLP-1 (A-B), where A is an integer from 1 to 7 and B is an integer from 38 to 45, optionally with one or more amino acid substitutions as defined below.

As an overview, after processing in the intestinal L-cells, GLP-1 is released into the circulation, most notably in response to a meal. The plasma concentration of GLP-1 rises from a fasting level of approximately 15 pmol/L to a peak postprandial level of 40 pmol/L. For a given rise in plasma glucose concentration, the increase in plasma insulin is approximately threefold greater when glucose is administered orally compared with intravenously (Kreymann et al., 1987, Lancet 2(8571): 1300-4). This alimentary enhancement of insulin release, known as the incretin effect, is primarily humoral and GLP-1 is now thought to be the most potent physiological incretin in humans. GLP-1 mediates insulin production via binding to the GLP-1 receptor, known to be expressed in pancreatic β cells. In addition to the insulinotropic effect, GLP-1 suppresses glucagon secretion, delays gastric emptying (Wettergen et al., 1993, Dig Dis Sci 38: 665-73) and may enhance peripheral glucose disposal (D'Alessio et al., 1994, J. Clin Invest 93: 2293-6).

A combination of actions gives GLP-1 unique therapeutic advantages over other agents currently used to treat non-insulin-dependent diabetes mellitus (NIDDM). First, a single subcutaneous dose of GLP-1 can completely normalize post prandial glucose levels in patients with NIDDM (Gutniak et al., 1994, Diabetes Care 17: 1039-44). This effect may be mediated both by increased insulin release and by a reduction in glucagon secretion. Second, intravenous infusion of GLP-1 can delay postprandial gastric emptying in patients with NIDDM (Williams et al., 1996, J. Clin Endo Metab 81: 327-32). Third, unlike sulphonylureas, the insulinotropic action of GLP-1 is dependent on plasma glucose concentration (Holz et al., 1993, Nature 361:362-5). Thus, the loss of GLP-1-mediated insulin release at low plasma glucose concentration protects against severe hypoglycemia.

When given to healthy subjects, GLP-1 potently influences glycemic levels as well as insulin and glucagon concentrations (Orskov, 1992, Diabetologia 35:701-11), effects which are glucose dependent (Weir et al., 1989, Diabetes 38: 338-342). Moreover, it is also effective in patients with diabetes (Gutniak, M., 1992, N. Engl J Med 226: 1316-22), normalizing blood glucose levels in type 2 diabetic subjects and improving glycemic control in type 1 patients (Nauck et al., 1993, Diabetologia 36: 741-4, Creutzfeldt et al., 1996, Diabetes Care 19:580-6).

GLP-1 is, however, metabolically unstable, having a plasma half-life (t_(1/2)) of only 1-2 minutes in vivo. Moreover, exogenously administered GLP-1 is also rapidly degraded (Deacon et al., 1995, Diabetes 44: 1126-31). This metabolic instability has limited the therapeutic potential of native GLP-1.

GLP-1[7-36]NH₂ has the following amino acid sequence: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 13), which may be employed as the GLP-1 component in accordance with the invention. Alternatively, the GLP-1 component may contain glycine (G) at the second position, giving, for example, the sequence HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 17). The GLP-1 component may be a biologically active fragment of GLP-1, for example, as disclosed in US 2007/0041951, which is hereby incorporated by reference in its entirety. Other fragments and modified sequences of GLP-1 are known in the art (U.S. Pat. Nos. 5,614,492; 5,545,618; European Patent Application, Publication No. EP 0658568 A1; WO 93/25579, which are hereby incorporated by reference in their entireties). Such fragments and modified sequences may be used in connection with the present invention, as well as those described below.

Certain structural and functional analogs of GLP-1 have been isolated from the venom of the Gila monster lizards (Heloderma suspectum and Heloderma horridum) and have shown clinical utility. Such molecules find use in accordance with the present invention. In particular, exendin-4 is a 39 amino acid residue peptide isolated from the venom of Heloderma suspectum and shares approximately 52% homology with human GLP-1. Exendin-4 is a potent GLP-1 receptor agonist that stimulates insulin release, thereby lowering blood glucose levels. Exendin-4 has the following amino acid sequence: HGEGTFTSDLSKQMEEEAVRLFEWLKNGGPSSGAPPPS (SEQ ID NO: 14). A synthetic version of exendin-4 known as exenatide (marketed as Byetta®) has been approved for the treatment of Type-2 Diabetes. Although exenatide is structurally analogous to native GLP-1, it has a longer half-life after injection.

While exenatide has the ability to lower blood glucose levels on its own, it can also be combined with other medications such as metformin, a thiozolidinedione, a sulfonylureas, and/or insulin to improve glucose control. Exenatide is administered by injection subcutaneously twice per day using a pre-filled pen device. Typical human responses to exenatide include improvements in the initial rapid release of endogenous insulin, an increase in β-cell growth and replication, suppression of pancreatic glucagon release, delayed gastric emptying, and reduced appetite—all of which function to lower blood glucose. Unlike sulfonylureas and meglitinides, exenatide increases insulin synthesis and secretion in the presence of glucose only, thus lessening the risk of hypoglycemia. Despite the therapeutic utility of exenatide, it has certain undesirable traits, including the requirement of twice daily injections, gastrointestional side effects, and similar to native GLP-1, a relatively short half-life (i.e. approximately 2 hr).

Various functional analogs of GLP-1 and exendin-4 are known, and which find use in accordance with the invention. These include liraglutide (Novo Nordisk, WO98/008871), R1583/taspoglutide (Roche, WO00/034331), CJC-1131 (ConjuChem, WO00/069911), ZP-10/AVE0010 (Zealand Pharma, Sanofi-Aventis, WO01/004156), and LY548806 (Eli Lilly, WO03/018516).

Liraglutide, also known as NN2211, is a GLP-1 receptor agonist analog that has been designed for once-daily injection (Harder et al., 2004, Diabetes Care 27: 1915-21). Liraglutide has been tested in patients with type-2 diabetes in a number of studies and has been shown to be effective over a variety of durations. In one study, treatment with liraglutide improved glycemic control, improved β-cell function, and reduced endogenous glucose release in patients with type-2 diabetes after one week of treatment (Degn et al., 2004, Diabetes 53: 1187-94). In a similar study, eight weeks of 0.6-mg liraglutide therapy significantly improved glycemic control without increasing weight in subjects with type 2 diabetes compared with those on placebo (Harder et al., 2004, Diabetes Care 27: 1915-21).

Thus, in certain embodiments, the GLP-1 receptor agonist in accordance with the invention is as described in WO98/008871, which is hereby incorporated by reference in its entirety. The GLP-1 receptor agonist may have at least one lipophilic substituent, in addition to one, two, or more amino acid substitutions with respect to native GLP-1. For example, the lipophilic substituent may be an acyl group selected from CH₃(CH₂)_(n)CO—, wherein n is an integer from 4 to 38, such as an integer from 4 to 24. The lipophilic substituent may be an acyl group of a straight-chain or branched alkyl or fatty acid (for example, as described in WO98/008871, which description is hereby incorporated by reference).

In certain embodiments, the GLP-1 component is Arg²⁶-GLP-1 (7-37), Arg³⁴-GLP-1(7-37), Lys³⁶-GLP-1 (7-37), Arg^(26,34)Lys³⁶-GLP-I (7-37), Arg^(26,34)Lys³⁶-GLP-1 (7-38), Arg^(28,34) Lys³⁹-GLP-1 (7-39), Arg^(26,34)Lys⁴⁰-GLP-1(7-40), Arg²⁶Lys³⁶-GLP-1(7-37), Arg³⁴Lys³⁶-GLP-1(7-37), Arg²⁶Lys³⁹-GLP-1(7-39), Arg³⁴Lys⁴⁰-GLP-1(7-40), Arg^(26,34)Lys^(36,39)-GLP-I (7-39), Arg^(26,34)Lys^(36,40)-GLP-1(7-40), Gly⁸Arg²⁶-GLP-1(7-37); Gly⁸Arg³⁴-GLP-1(7-37); Gly⁸Lys³⁸-GLP-1(7-37); Gly⁸Arg^(26,34)Lys³⁶-GLP-1(7-37), Gly⁸Arg^(26,34)Lys³⁹-GLP-1(7-39), Gly⁸Arg^(26,34)Lys⁴⁰-GLP-1(7-40), Gly⁸Arg²⁶Lys³⁶-GLP-1(7-37), Gly⁸Arg³⁴Lys³⁶-GLP-1(7-37), Gly⁸Arg²⁶Lys³⁹-GLP-1(7-39); Gly⁸Arg³⁴Lys⁴⁰-GLP-1(7-40), Gly⁸Arg^(26,34)Lys^(36,39)GLP-1(7-39) and Gly⁸Arg^(26,34)Lys^(35,40)-GLP-1(7-40), each optionally having a lipophilic substituent. For example, the GLP-1 receptor agonist may have the sequence/structure Arg³⁴Lys²⁶-(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37).

Taspoglutide, also known as R1583 or BIM 51077, is a GLP-1 receptor agonist that has been shown to improve glycemic control and lower body weight in subjects with type 2 diabetes mellitus treated with metformin (Abstract No. A-1604, Jun. 7, 2008, 68th American Diabetes Association Meeting, San Francisco, Calif.).

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO00/034331, which is hereby incorporated by reference in its entirety. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence [Aib^(8,35)]hGLP-1(7-36)NH₂ (e.g. taspoglutide), wherein Aib is alpha-aminoisobutyric acid.

CJC-1131 is a GLP-1 analog that consists of a DPP-IV-resistant form of GLP-1 joined to a reactive chemical linker group that allows GLP-1 to form a covalent and irreversible bond with serum albumin following subcutaneous injection (Kim et al., 2003, Diabetes 52: 751-9). In a 12-week, randomized, double-blind, placebo-controlled multicenter study, CJC-1131 and metformin treatment was effective in reducing fasting blood glucose levels in type 2 diabetes patients (Ratner et al., Abstract No. 10-OR, Jun. 10-14, 2005, 65th American Diabetes Association Meeting, San Francisco, Calif.).

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO00/069911, which is hereby incorporated by reference in its entirety. In some embodiments, the GLP-1 receptor agonist is modified with a reactive group which reacts with amino groups, hydroxyl groups or thiol groups on blood components to form a stable covalent bond. In certain embodiments, the GLP-1 receptor agonist is modified with a reactive group selected from the group consisting of succinimidyl and maleimido groups. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence/structure: D-Ala⁸Lys³⁷-(2-(2-(2-maleimidopropionamido(ethoxy)ethoxy)acetamide))-GLP-1(7-37) (e.g. CJC-1131).

AVE0010, also known as ZP-10, is a GLP-1 receptor agonist that may be employed in connection with the invention. In a recent double-blind study, patients treated with once daily dosing of AVE0010 demonstrated significant reductions in HbA1c levels (Ratner et al., Abstract No. 433-P, 68th American Diabetes Association Meeting, San Francisco, Calif.). At the conclusion of the study, the percentages of patients with HbA1c <7% ranged from 47-69% for once daily dosing compared to 32% for placebo. In addition, AVE0010 treated patients showed dose-dependent reductions in weight and post-prandial plasma glucose.

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO01/004156, which is hereby incorporated by reference in its entirety. For example, the GLP-1 receptor agonist may have the sequence:

(SEQ ID NO: 18) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2. (e.g. AVE0010)

LY548806 is a GLP-1 derivative designed to be resistant to proteolysis by dipeptidase-peptidyl IV (DPP-IV) (Jackson et al., Abstract No. 562, Jun. 10-14, 2005, 65th American Diabetes Association Meeting, San Francisco, Calif.). In an animal model of hyperglycemia, LY548806 has been shown to produce a significant lowering of blood glucose levels during the hyperglycemic phase (Saha et al., 2006, J. Pharm. Exp. Ther. 316: 1159-64). Moreover, LY548806 was shown to produce a significant increase in insulin levels consistent with its known mechanism of action, namely stimulation of insulin release in the presence of hyperglycemia.

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO03/018516, which is hereby incorporated by reference in its entirety. In some embodiments, the therapeutic agents of the present invention comprise GLP-1 analogs wherein the backbone for such analogs or fragments contains an amino acid other than alanine at position 8 (position 8 analogs). The backbone may also include L-histidine, D-histidine, or modified forms of histidine such as desamino-histidine, 2-amino-histidine, s-hydroxy-histidine, homohistidine, α-fluoromethyl-histidine, or α-methyl-histidine at position 7. In some embodiments, these position 8 analogs may contain one or more additional changes at positions 12, 16, 18, 19, 20, 22, 25, 27, 30, 33, and 37 compared to the corresponding amino acid of native GLP-1. In other embodiments, these position 8 analogs may contain one or more additional changes at positions 16, 18, 22, 25 and 33 compared to the corresponding amino acid of native GLP-1. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence: HVEGTFTSDVSSYLEEQAAKEFIAWLIKGRG-OH (SEQ ID NO: 19) (e.g. LY548806).

Thus, the present invention provides therapeutic agents comprising an elastin-like peptide (ELP) and a GLP-1 receptor agonist. For example, in certain embodiments, the GLP-1 receptor agonist is GLP-1 (SEQ ID NO:13, 17, or 59) or a functional analog thereof. In other embodiments, the GLP-1 receptor agonist is exendin-4 (SEQ ID NO:14) or a functional analog thereof. Such functional analogs of GLP-1 or exendin-4 include functional fragments truncated at the C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, or up to about 5 amino acids (with respect to SEQ ID NOS: 13, 14, 17, or 59). Such functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NOS 13, 14, and 59), and in each case retaining the activity of the peptide. For example, the functional analog of GLP-1 or exendin-4 may have from 1 to about 3, 4, or 5 insertions, deletions and/or substitutions (collectively) with respect to SEQ ID NOS: 13, 59 and 14, and in each case retaining the activity of the peptide. Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the GLP-1 receptor agonist component has at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the native sequence (SEQ ID NOS: 13, 59, and 14). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences—a new tool for comparing protein and nucleotide sequences, FEMS Miarobiol Left. 174:247-250 (1999). Such functional analogs may further comprise additional chemical modifications, such as those described in this section and/or others known in the art.

In certain embodiments, the GLP1-ELP fusion has a sequence exemplified herein as SEQ ID NOS: 54 and 56. When processed, the mature form of such fusion protein will begin with the His⁷ of GLP.

In another aspect, the present invention provides methods for the treatment or prevention of type 2 diabetes, impaired glucose tolerance, type 1 diabetes, hyperglycemia, obesity, binge eating, bulimia, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, non-fatty liver disease, myocardial infarction, coronary heart disease and other cardiovascular disorders. The method comprises administering the therapeutic agent comprising the elastin-like peptide (ELP) and the GLP-1 receptor agonist (as described above) to a patient in need of such treatment. In these or other embodiments, the present invention provides methods for decreasing food intake, decreasing β-cell apoptosis, increasing β-cell function and β-cell mass, and/or for restoring glucose sensitivity to β-cells. Generally, the patient may be a human or non-human animal patient (e.g., dog, cat, cow, or horse). Preferably, the patient is human.

The treatment with a ELP/GLP-1 receptor agonist compound according to the present invention may also be combined with one or more pharmacologically active substances, e.g. selected from antidiabetic agents, antiobesity agents, appetite regulating agents, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity. In the present context, the expression “antidiabetic agent” includes compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism.

The ability of a GLP-1 or exendin-4 analog, or an GLP-1 receptor agonist/ELP compound, to bind the GLP-1 receptor may be determined by standard methods, for example, by receptor-binding activity screening procedures which involve providing appropriate cells that express the GLP-1 receptor on their surface, for example, insulinoma cell lines such as RINmSF cells or INS-1 cells. In addition to measuring specific binding of tracer to membrane using radioimmunoassay methods, cAMP activity or glucose dependent insulin production can also be measured. In one method, a polynucleotide encoding the GLP-1 receptor is employed to transfect cells to thereby express the GLP-1 receptor protein. Thus, these methods may be employed for testing or confirming whether a suspected GLP-1 receptor agonist is active. An exemplary assay is described in greater detail herein.

In addition, known methods can be used to measure or predict the level of biologically activity of a GLP-1 receptor agonist or GLP-1 receptor agonist/ELP in vivo (See e.g. Siegel, et al., 1999, Regul Pept 79(2-3): 93-102). In particular, GLP-1 receptor agonists or GLP-1 receptor agonist/ELP compounds can be assessed for their ability to induce the production of insulin in vivo using a variety of known assays for measuring GLP-1 activity. For example, an ELP/GLP-1 receptor agonist compound can be introduced into a cell, such as an immortalized β-cell, and the resulting cell can be contacted with glucose. If the cell produces insulin in response to the glucose, then the modified GLP-1 is generally considered biologically active in vivo (Fehmann et al., 1992, Endoarinology 130: 159-166). An exemplary assay is described in greater detail herein.

The ability of an GLP-1 receptor agonist/ELP compound to enhance β-cell proliferation, inhibit β-cell apoptosis, and regulate islet growth may also be measured using known assays. Pancreatic β-cell proliferation may be assessed by ³H-tymidine or BrdU incorporation assays (See e.g. Buteau et al., 2003, Diabetes 52: 124-32), wherein pancreatic β-cells such as INS(832/13) cells are contacted with an ELP/GLP-1 receptor agonist compound and analyzed for increases in ³H-thymidine or BrdU incorporation. The antiapoptotic activity of an ELP/GLP-1 receptor agonist compound can be measured in cultured insulin-secreting cells and/or in animal models where diabetes occurs as a consequence of an excessive rate of beta-cell apoptosis (See e.g. Bulotta et al., 2004, Cell Biochem Biophys 40(3 suppl): 65-78).

In addition to GLP-1, other peptides of this family, such as those derived from processing of the pro-glucagon gene, such as GLP-2, GIP, and oxyntomodulin, could be conjugated or fused to the ELP component (as described herein) to enhance the therapeutic potential.

Insulin

In other embodiments, the present invention provides a therapeutic agent comprising an ELP component coupled to insulin (e.g., via fusion or conjugation). Insulin injections, e.g. of human insulin, can be used to treat diabetes. The insulin-making cells of the body are called β-cells, and they are found in the pancreas gland. These cells clump together to form the “islets of Langerhans”, named for the German medical student who described them.

The synthesis of insulin begins at the translation of the insulin gene, which resides on chromosome 11. During translation, two introns are spliced out of the mRNA product, which encodes a protein of 110 amino acids in length. This primary translation product is called preproinsulin and is inactive. It contains a signal peptide of 24 amino acids in length, which is required for the protein to cross the cell membrane.

Once the preproinsulin reaches the endoplasmic reticulum, a protease cleaves off the signal peptide to create proinsulin. Proinsulin consists of three domains: an amino-terminal B chain, a carboxyl-terminal A chain, and a connecting peptide in the middle known as the C-peptide. Insulin is composed of two chains of amino acids named chain A (21 amino acids-GIVEQCCASVCSLYQLENYCN) (SEQ ID NO: 15) and chain B (30 amino acids FVNQHLCGSHLVEALYLVCGERGFFYTPKA) (SEQ ID NO: 16) that are linked together by two disulfide bridges. There is a 3rd disulfide bridge within the A chain that links the 6th and 11th residues of the A chain together. In most species, the length and amino acid compositions of chains A and B are similar, and the positions of the three disulfide bonds are highly conserved. For this reason, pig insulin can replace deficient human insulin levels in diabetes patients. Today, porcine insulin has largely been replaced by the mass production of human proinsulin by bacteria (recombinant insulin).

Insulin molecules have a tendency to form dimers in solution, and in the presence of zinc ions, insulin dimers associate into hexamers. Whereas monomers of insulin readily diffuse through the blood and have a rapid effect, hexamers diffuse slowly and have a delayed onset of action. In the design of recombinant insulin, the structure of insulin can be modified in a way that reduces the tendency of the insulin molecule to form dimers and hexamers but that does not interrupt binding to the insulin receptor. In this way, a range of preparations are made, varying from short acting to long acting.

Within the endoplasmic reticulum, proinsulin is exposed to several specific peptidases that remove the C-peptide and generate the mature and active form of insulin. In the Golgi apparatus, insulin and free C-peptide are packaged into secretory granules, which accumulate in the cytoplasm of the β-cells. Exocytosis of the granules is triggered by the entry of glucose into the beta cells. The secretion of insulin has a broad impact on metabolism.

There are two phases of insulin release in response to a rise in glucose. The first is an immediate release of insulin. This is attributable to the release of preformed insulin, which is stored in secretory granules. After a short delay, there is a second, more prolonged release of newly synthesized insulin.

Once released, insulin is active for a only a brief time before it is degraded by enzymes. Insulinase found in the liver and kidneys breaks down insulin circulating in the plasma, and as a result, insulin has a half-life of only about 6 minutes. This short duration of action results in rapid changes in the circulating levels of insulin.

Insulin analogs have been developed with improved therapeutic properties (Owens et al., 2001, Lancet 358: 739-46; Vajo et al., 2001, Endocr Rev 22: 706-17), and such analogs may be employed in connection with the present invention. Various strategies, including elongation of the COOH-terminal end of the insulin B-chain and engineering of fatty acid-acylated insulins with substantial affinity for albumin are used to generate longer-acting insulin analogs. However, in vivo treatments with available longer-acting insulin compounds still result in a high frequency of hypo- and hyperglycemic excursions and modest reduction in HbA_(1c). Accordingly, development of a truly long-acting and stable human insulin analog still remains an important task.

Functional analogs of insulin that may be employed in accordance with the invention include rapid acting analogs such as lispro, aspart and glulisine, which are absorbed rapidly (<30 minutes) after subcutaneous injection, peak at one hour, and have a relatively short duration of action (3 to 4 hours). In addition, two long acting insulin analogs have been developed: glargine and detemir, and which may be employed in connection with the invention. The long acting insulin analogs have an onset of action of approximately two hours and reach a plateau of biological action at 4 to 6 hours, and may last up to 24 hours.

Thus, in one embodiment, the insulin component may contain the A and/or B chain of lispro (also known as Humalog, Eli Lilly). Insulin lispro differs from human insulin by the substitution of proline with lysine at position 28 and the substitution of lysine with proline at position 29 of the insulin B chain. Although these modifications do not after receptor binding, they help to block the formation of insulin dimers and hexamers, allowing for larger amounts of active monomeric insulin to be available for postprandial injections.

In another embodiment, the insulin may contain an A and/or B chain of aspart (also known as Novolog, Novo Nordisk). Insulin aspart is designed with the single replacement of the amino acid proline by aspartic acid at position 28 of the human insulin B chain. This modification helps block the formation for insulin hexamers, creating a faster acting insulin.

In yet another embodiment, the insulin may contain an A and/or B chain of glulisine (also known as Apidra, Sanofi-Aventis). Insulin glulisine is a short acting analog created by substitution of asparagine at position 3 by lysine and lysine at position 29 by glutamine of human insulin B chain. Insulin glulisine has more rapid onset of action and shorter duration of action compared to regular human insulin.

In another embodiment, the insulin may contain an A and/or B chain of glargine (also known as Lantus, Sanofi-Aventis). Insulin glargine differs from human insulin in that the amino acid asparagine at position 21 of the A chain is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Compared with bedtime neutral protamine Hagedom (NPH) insulin (an intermediate acting insulin), insulin glargine is associated with less noctumal hypoglycemia in patients with type 2 diabetes.

In yet another embodiment, the insulin may contain an A and/or B chain from detemir (also known as Levemir, Novo Nordisk). Insulin detemir is a soluble (at neutral pH) long-acting insulin analog, in which the amino acid threonine at B30 is removed and a 14-carbon, myristoyl fatty acid is acetylated to the epsilon-amino group of LysB29. After subcutaneous injection, detemir dissociates, thereby exposing the free fatty acid which enables reversible binding to albumin molecules. So at steady state, the concentration of free unbound insulin is greatly reduced resulting in stable plasma glucose levels.

In some embodiments, the insulin may be a single-chain insulin analog (SIA) (e.g. as described in U.S. Pat. No. 6,630,438 and WO08/019368, which are hereby incorporated by reference in their entirety). Single-chain insulin analogs encompass a group of structurally-related proteins wherein the A and B chains are covalently linked by a polypeptide linker. The polypeptide linker connects the C-terminus of the B chain to the N-terminus of the A chain. The linker may be of any length so long as the linker provides the structural conformation necessary for the SIA to have a glucose uptake and insulin receptor binding effect. In some embodiments, the linker is about 5-18 amino acids in length. In other embodiments, the linker is about 9-15 amino acids in length. In certain embodiments, the linker is about 12 amino acids long. In certain exemplary embodiments, the linker has the sequence KDDNPNLPRLVR (SEQ ID NO.: 20) or GAGSSSRRAPQT (SEQ ID NO.: 21). However, it should be understood that many variations of this sequence are possible such as in the length (both addition and deletion) and substitutions of amino acids without substantially compromising the effectiveness of the produced SIA in glucose uptake and insulin receptor binding activities. For example, several different amino acid residues may be added or removed from either end without substantially decreasing the activity of the produced SIA.

An exemplary single-chain insulin analog currently in clinical development is albulin (Duttaroy et al., 2005, Diabetes 54: 251-8). Albulin can be produced in yeast or in mammalian cells. It consists of the B and A chain of human insulin (100% identity to native human insulin) linked together by a dodecapeptide linker and fused to the NH₂ terminals of the native human serum albumin. For expression and purification of albulin, Duttaroy et al. constructed a synthetic gene construct encoding a single-chain insulin containing the B- and A-chain of mature human insulin linked together by a dodecapeptide linker using four overlapping primers and PCR amplification. The resulting PCR product was ligated in-frame between the signal peptide of human serum albumin (HSA) and the NH₂ terminus of mature HSA, contained within a pSAC35 vector for expression in yeast. In accordance with the present invention, the HSA component of abulin may be replaced with an ELP component as described herein.

Thus, in one aspect, the present invention provides therapeutic agents comprising an elastin-like peptide (ELP) and an insulin or functional analog thereof. For example, in certain embodiments, the insulin is a mammalian insulin, such as human insulin or porcine insulin. In accordance with the invention, the ELP component may be coupled (e.g., via recombinant fusion or chemical conjugation) to the insulin A chain, or B chain, or both. The insulin may comprise each of chains A, B, and C (SEQ ID NOS: 51 and 52), or may contain a processed form, containing only chains A and B. In some embodiments, chains A and B are connected by a short linking peptide, to create a single chain insulin. The insulin may be a functional analog of human insulin, including functional fragments truncated at the N-terminus and/or C-terminus (of either or both of chains A and B) by from 1 to 10 amino acids, including by 1, 2, 3, or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NOS 15 and 16), and in each case retaining the activity of the peptide. For example, functional analogs may have 1, 2, 3, 4, or 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (which may contain chains A and B, or chains A, B, and C). Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the insulin component has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with each of the native sequences for chains A and B (SEQ ID NOS:15 and 16). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences—a new tool for comparing protein and nucleotide seguences. FEMS Microbiol Left. 174:247-250 (1999). The insulin component may contain additional chemical modifications known in the art.

In another aspect, the present invention provides methods for the treatment or prevention of diabetes, including type I and II diabetes. The method comprises administering an effective amount of the therapeutic agent comprising an elastin-like peptide (ELP) component and an insulin (or functional analog thereof) component to a patient in need thereof. Generally, the patient may be a human or non-human animal (e.g., dog, cat, cow, or horse) patient. Preferably, the patient is human.

To characterize the in vitro binding properties of an insulin analog or an ELP-containing insulin analog, competition binding assays may be performed in various cell lines that express the insulin receptor (Jehle et al., 1996, Diabetologia 39: 421-432). For example, competition binding assays using CHO cells overexpressing the human insulin receptor may be employed. Insulin can also bind to the IGF-1 receptor with a lower affinity than the insulin receptor. To determine the binding affinity of an ELP-containing insulin analog, a competition binding assay can be performed using ¹²⁵I-labeled IGF-1 in L6 cells.

The activities of insulin include stimulation of peripheral glucose disposal and inhibition of hepatic glucose production. The ability of an ELP-containing insulin analog to mediate these biological activities can be assayed in vitro using known methodologies. For example, the effect of an ELP-containing analog on glucose uptake in 3T3-L1 adipocytes can be measured and compared with that of insulin. Pretreatment of the cells with a biologically active analog will generally produce a dose-dependent increase in 2-deoxyglucose uptake. The ability of an ELP-containing insulin analog to regulate glucose production may be measured in any number of cells types, for example, H4IIe hepatoma cells. In this assay, pretreatment with a biologically active analog will generally result in a dose-dependent inhibition of the amount of glucose released.

Factor VII (VIIa)

In certain embodiments, the invention provides therapeutic agents comprising an ELP component coupled (e.g., via fusion or conjugation) to a Factor VII/VIIa. Coagulation is the biological process of blood clot formation involving many different serine proteases as well as their essential cofactors and inhibitors. It is initiated by exposure of Factor VII (FVII) and Factor VIIa (FVIIa) to its membrane bound cofactor, tissue factor (TF), resulting in production of Factor Xa (FXa) and more FVIIa. The process is propagated upon production of Factor IXa (FIXa) and additional FXa that, upon binding with their respective cofactors FVIIIa and FVa, form platelet bound complexes, ultimately resulting in the formation of thrombin and a fibrin clot. Thrombin also serves to further amplify coagulation by activation of cofactors such as FV and FVII and zymogens such as Factor XI. Moreover, thrombin activates platelets leading to platelet aggregation, which is necessary for the formation of a hemostatic plug.

Factor VII circulates in the blood in a zymogen form, and is converted to its active form, Factor VIIa, by either factor IXa, factor Xa, factor XIIa, or thrombin by minor proteolysis. Factor VIIa is a two-chain, 50 kilodalton (kDa) plasma serine protease. The active form of the enzyme comprises a heavy chain (254 amino acid residues) containing a catalytic domain and a light chain (152 residues) containing 2 epidermal growth factor (EGF)-like domains. The mature factor VII/VIIa that circulates in plasma is composed of 406 amino acid residues (SEQ ID NO: 33). The light and heavy chains are held together by a disulfide bond.

As noted above, Factor VIIa is generated by proteolysis of a single peptide bond from its single chain zymogen, Factor VII, which is present at approximately 0.5 μg/ml in plasma. The conversion of zymogen Factor VII into the activated two-chain molecule occurs by cleavage of an internal peptide bond. In human Factor VII, the cleavage site is at Arg152-Ile153 (Hagen et al., 1986, PNAS USA 83: 2412-6).

“Factor VII/VIIa” as used in this application means a product consisting of either the unactivated form (factor VII) or the activated form (factor VIIa) or mixtures thereof. “Factor VII/VIIa” within the above definition includes proteins that have an amino acid sequence of native human factor VII/VIIa. It also includes proteins with a slightly modified amino acid sequence, for instance, a modified N-terminal end including N-terminal amino acid deletions or additions so long as those proteins substantially retain the activity of factor VIIa. “Factor VII” within the above definition also includes natural allelic variations that may exist and occur from one individual to another. Also, degree and location of glycosylation or other post-translation modifications may vary depending on the chosen host cells and the nature of the host cellular environment.

In the presence of calcium ions, Factor VIIa binds with high affinity to TF. TF is a 263 amino acid residue glycoprotein composed of a 219 residue extracellular domain, a single transmembrane domain, and a short cytoplasmic domain (Morrissey et al., 1987, Cell 50: 129-35). The TF extracellular domain is composed of two fibronectin type Ill domains of about 105 amino acids each. The binding of FVIIa is mediated entirely by the TF extracellular domain (Muller et al., 1994, Biochem. 33:10864-70). Residues in the area of amino acids 16-26 and 129-147 contribute to the binding of FVIIa as well as the coagulant function of the molecule. Residues Lys20, Trp45, Asp58, Tyr94, and Phe140 make a large contribution (1 kcal/mol) to the free energy (ΔG) of binding to FVIIa.

TF is expressed constitutively on cells separated from plasma by the vascular endothelium. Its expression on endothelial cells and monocytes is induced by exposure to inflammatory cytokines or bacterial lipopolysacchardes (Drake et al., 1989, J. Cell Biol. 109: 389). Upon tissue injury, the exposed extracellular domain of TF forms a high affinity, calcium dependent complex with FVII. Once bound to TF, FVII can be activated by peptide bond cleavage to yield serine protease FVIIa. The enzyme that catalyzes this step in vivo has not been elucidated, but in vitro FXa, thrombin, TF:FVIIa and FIXa can catalyze this cleavage. FVIIa has only weak activity upon its physiological substrates FX and FIX whereas the TF:FVIIa complex rapidly activates FX and FIX.

The TF:FVIIa complex constitutes the primary initiator of the extrinsic pathway of blood coagulation. The complex initiates the extrinsic pathway by activation of FX to Factor Xa (FXa), FIX to Factor IXa (FIXa), and additional FVII to FVIIa. The action of TF:FVIIa leads ultimately to the conversion of prothrombin to thrombin, which carries out many biological functions. Among the most important activities of thrombin is the conversion of fibrinogen to fibrin, which polymerizes to form a clot. The TF:FVIIa complex also participates as a secondary factor in extending the physiological effects of the contact activation system.

The initiation and subsequent regulation of coagulation is complex, since maintenance of hemostasis is crucial for survival. There is an exquisite balance between hemostasis (normal clot formation and dissolution) and thrombosis (pathogenic clot formation). Serious clinical conditions involving aberrations in coagulation include deep vein thrombosis, myocardial infarction, pulmonary embolism, stroke and disseminated intravascular coagulation (in sepsis). There are also many bleeding coagulopathies where there is insufficient clot formation. These include hemophilia A (FVIII deficiency) or hemophilia B (FIX deficiency), where procoagulant therapy is required. The challenge in this therapeutic area is to operate in the narrow window between too much and too little coagulation.

The use of exogenous FVIIa as a therapeutic agent has been shown to induce hemostasis in patients with hemophilia A and B (Hedner, 2001, Seminars Hematol. 38 (suppl. 12): 43-7; Hedner, 2004, Seminars Hematol. 41 (suppl. 1): 35-9). It also has been used to treat bleeding in patients with liver disease, anticoagulation-induced bleeding, surgery, thrombocytopenia, thrombasthenia, Bemard-Soulier syndrome, von Willebrand disease, and other bleeding disorders (See e.g. Roberts et al., 2004, Blood 104: 3858-64).

Commercial preparations of human recombinant FVIIa are sold as NovoSeven.™ NovoSeven™ is indicated for the treatment of bleeding episodes in hemophilia A or B patients and is the only recombinant FVIIa effective for bleeding episodes currently available. A circulating recombinant FVIIa half-life of 2.3 hours was reported in “Summary Basis for Approval for NovoSevenm” FDA reference number 96-0597. Moreover, the half-life of recombinant FVIIa is shorter in pediatric patients (˜1.3 hours), suggesting that higher doses of recombinant FVIIa may be required in this population (Roberts et al., 2004, Blood 104: 3858-64). Accordingly, relatively high doses and frequent administration are necessary to reach and sustain the desired therapeutic or prophylactic effect. As a consequence, adequate dose regulation is difficult to obtain and the need of frequent intravenous administrations imposes restrictions on the patient's way of living.

A molecule with a longer circulation half-life would decrease the number of necessary administrations. Given the frequent injections associated with currently available FVIIa therapy and the potential for obtaining more optimal therapeutic FVIIa levels with concomitant enhanced therapeutic effect, there is a clear need for improved FVII or FVIIa-like molecules with a longer half-life in vivo.

Recombinant human coagulation factor VIIa (rFVIIa, NovoSeven; Novo Nordisk A/S, Copenhagen, Denmark) has proven to be efficacious for the treatment of bleeding episodes in hemophilia patients with inhibitors. A small fraction of patients may be refractory to rFVIIa treatment and could potentially benefit from genetically modified FVIIa molecules with increased potencies. To this end, FVIIa analogs with increased intrinsic activity have been investigated that exhibit superior hemostatic profiles in vitro (see e.g. WO02/077218 or WO05/074975, which are hereby incorporated by reference in their entirety, and Tranholm et al., 2003, Blood 102(10): 3615-20, which is also incorporated by reference). These analogs may also be used as more efficacious hemostatic agents in other indications where efficacy of rFVIIa has been observed, including in thrombocytopenia and trauma.

Thus, in some embodiments, the Factor VIIa analog that may be used in accordance with the invention is as described in WO02/077218 or WO05/074975. For example, the FVIIa analog may have a glutamine substituted for methionine at position 298 (i.e. M298Q-FVIIa). In certain exemplary embodiments, the FVIIa analog contains two additional mutations, valine at position 158 replaced by aspartic acid and glutamic acid at position 296 replaced by valine (i.e. V158D/E296V/M298Q-FVIIa). Additionally or alternatively, the Factor VIIa analog may have an alanine residue substitution for lysine at position 337 (i.e. V158D/E296V/M298Q/K337A-FVIIa). In still other embodiments, the Factor VIIa analog has a substitution or insertion selected from Q250C; P406C; and 407C, wherein a cysteine has also been introduced in the C-terminal sequence (see, e.g. U.S. Pat. No. 7,235,638, which is hereby incorporated by reference in its entirety). The Factor VIIa analog may further comprise a substitution or insertion at one or more of positions 247, 260, 393, 396, and/or 405.

In these or other embodiments, the Factor VIIa analog comprises a substitution relative to the sequence of native Factor VIIa selected from: (a) a substitution of Lys157 with an amino acid selected from the group consisting of Gly, Val, Ser, Thr, Asp, and Glu; (b) a substitution of Lys337 with an amino acid selected from the group consisting of Ala, Gly, Val, Ser, Thr, GIn, Asp, and Glu; (c) a substitution of Asp334 with any amino acid other than Ala or Asn; and (d) a substitution of Ser336 with any amino acid other than Ala or Cys (see e.g. U.S. Pat. No. 7,176,288, which is hereby incorporated by reference in its entirety). Additionally or alternatively, the Factor VIIa analog comprises a substitution of the Leu at position 305 of Factor VII with an amino acid residue selected from the group consisting of Val, lie, Met, Phe, Trp, Pro, Gly, Ser, Thr, Cys, Tyr, Asn, Glu, Lys, Arg, His, Asp and GIn (see e.g. U.S. Pat. No. 6,905,683, which is hereby incorporated by reference in its entirety).

Thus, in one aspect, the present invention provides therapeutic agents comprising an elastin-like peptide (ELP) and a Factor VII/VIIa, or functional analog thereof. For example, in certain embodiments, the Factor VII/VIIa is human Factor VII/VIIa (e.g., SEQ ID NO: 33). The Factor VII/VIIa may be a functional analog of human Factor VII/VIIa, including functional fragments truncated at the N-terminus and/or C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NO: 33), and in each case retaining the activity of the peptide. For example, such analogs may have from 1 to about 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native full length sequence, or with respect to one or both of the heavy and light chains. Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the Factor VII/VIIa component has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with the native sequence (SEQ ID NO:33). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences —a new tool for comparing protein and nucleotide sequences, FEMS Microbiol Left. 174:247-250 (1999).

In exemplary embodiments, the FactorVII-ELP fusion has the amino acid sequence of SEQ ID NO:58. SEQ ID NO:58 further comprises a TEV protease cleavage site between the FactorVII and ELP sequences, which may be beneficial for removing the ELP sequence post expression where desired. However, in accordance with the invention, the tev sequence may be entirely removed, or replaced with another linking sequence as disclosed herein.

In another aspect, the present invention provides methods for the treatment or prevention of bleeding-related disorders. The method comprises administering an effective amount of the therapeutic agent comprising an elastin-like peptide (ELP) and a Factor VII/VIIa or functional analog thereof to a patient in need. In certain embodiments, the bleeding-related disorder is one or more of hemophilia (A or B), post-surgical bleeding, anticoagulation-induced bleeding, thrombocytopenia, Factor VII deficiency, Factor X deficiency, bleeding in patients with liver disease, thrombasthenia, Bemard-Soulier syndrome, von Willebrand disease, and intracranial hemorrhage. Generally, the patient is a human or non-human animal (e.g., dog, cat, cow, or horse) patient. Preferably, the patient is human.

To characterize the in vitro binding properties of a suspected Factor VII/VIIa analog, or an ELP-containing Factor VIIa analog, TF binding assays can be performed as described previously (See, e.g., Chaing et al., 1994, Blood 83(12): 3524-35). Briefly, recombinant human TF can be coated onto Immulon II plates in carbonate antigen buffer overnight at 4° C. BSA is also coated onto the plates for use as a control. ELP-containing Factor VIIa analogs may be added at various concentrations in TBS-T buffer. After several washes, monospecific polyclonal rabbit anti-human FVIIa sera is added and incubated for approximately an hour at room temperature. Next, goat anti-rabbit IgG conjugated to alkaline phosphatase is added, followed by the alkaline phosphatase substrate PNPP, which is used for detection. After subtraction of background, the absorbance at ˜405 nm is taken to be directly proportional to the degree of Factor VIIa binding to the immobilized TF. These values can then be compared to control plasma containing Factor VIIa.

The clotting ability of a Factor VII/VIIa analog or an ELP-containing Factor VIIa analog can be measured in human FVII deficient plasma. In this assay, the ELP-containing Factor VIIa analog diluted to varying concentrations directly into FVII deficient plasma. In a coagulometer, one part plasma± a FVIIa analog can be mixed with 2 parts Innovin™ (Dade, Miami, Fla.) prothrombin time reagent (recombinant human tissue factor with phospholipids and CaCl₂). Clot formation is detected optically and time to clotting measured. Clotting time (seconds) is compared to the mean clotting time of FVII-deficient plasma alone and plotted as the fractional clotting time versus FVIIa analog concentration.

Therapeutic Proteins

The present invention further provides therapeutic agents comprising an ELP component and at least one therapeutic protein selected from Table 1. The ELP component and therapeutic protein may be coupled by recombinant fusion or chemical conjugation as described herein. Such therapeutic proteins are listed in Table 1 by protein name and GeneSeq Accession No. The amino acid sequence of each Therapeutic Protein, which is known in the art, is hereby incorporated by reference for each Therapeutic Protein listed in Table 1. Such therapeutic proteins are further described in US patent or PCT publications that are also listed in Table 1, and such US patent and PCT publications are hereby incorporated by reference, especially with respect to the structure of such therapeutic proteins and described functional analogs.

Table 1 further describes the biological activity of each listed Therapeutic Protein, as well as an exemplary assay for determining the activity of functional analogs or agents of the invention (e.g., fusion with an ELP component). Generally, functional analogs of therapeutic proteins listed in Table 1 may include functional fragments truncated at the N-terminus and/or C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, 4 or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the base sequence (e.g., as listed in Table 1), and in each case retaining the full or partial biological activity (as listed in Table 1) of the therapeutic protein. For example, functional analogs may have 1, 2, 3, 4, or 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the base sequence. Such activity may be confirmed or assayed using any available assay, including those described in the Table. In these or other embodiments, the therapeutic protein has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with the corresponding base sequence. The molecules may further comprise additional chemical modifications known for each in the art.

In some embodiments, the therapeutic protein (e.g., as selected from Table 1) has a size of less than about 25 kDa, or less than about 10 kDa, or less than about 5 kDa, and the corresponding therapeutic agent of the invention (e.g., comprising the ELP component) has a molecular weight of less than about 60 kDa, 55 kDa, 50 kDa, or 40 kDa.

Table 1 further lists preferred indications for each therapeutic protein, for which the corresponding therapeutic agent finds use, such as in a method for treatment or prevention related to such indication.

TABLE 1 Exemplary Identifier PCT/Patent Reference Exemplary Activity Assay (the sequences listed in (the patents and publications (the publications listed in this Therapeutic this column are each hereby listed in this column are each column are each hereby incorporated Protein X incorporated by reference) hereby incorporated by reference) Biological Activity by reference) Preferred Indication Y BMP-1 GeneSeq Acession WO8800205 BMP1 belongs to the transforming BMP-1 activity can be determined Induction of Cartilage, P80618 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic proteins induce the art: Nat Genet. 2001 Growth, and Diabetes cartilage and bone formation, play January; 27(1): 84-8; Eur J Biochem 1996 important role in nephrogesis, and play Apr. 1; 237(1): 295-302; J Biol Chem, an important role in the development of Vol. 274, Issue 16, 10897-10902, many organs, including lung, heart, Apr. 16, 1999; and Hogan, B. L. M. teeth, gut, skin, and particularly the (1996) Genes Dev. 10, 1580-1594. kidney. BMP-2 GeneSeq Accession WO8800205 BMP-2 belongs to the transforming BMP-2 activity can be determined Induction of Cartilage, P80619 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-2B GeneSeq Accession U.S. Pat. No. 5,631,142 BMP-2b belongs to the transforming BMP-2b activity can be determined Induction of Cartilage, W24850 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; I Biol Cbcre, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-4 GeneSeq Accession WO0020591 BMP-4 belongs to the transforming BMP-4 activity can be determined Induction of Cartilage, B02796 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-5 GeneSeq Accession WO0020591 BMP-5 belongs to the transforming BMP-5 activity can be determined Induction of Cartilage, B02797 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-6 GeneSeq Accession U.S. Pat. No. 5,187,076 BMP-6 belongs to the transforming BMP-6 activity can be determined Induction of Cartilage, R32904 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Osteogenic GeneSeq Accession WO973462 OP-1 belongs to the transforming OP-1 activity can be determined Induction of Cartilage, Protein-1; OP-1; W34783 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone BMP-7 Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Osteogenic GeneSeq Accession WO9406399 OP-2 belongs to the transforming OP-2 activity can be determined Induction of Cartilage, Protein-2 R57973 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic Protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. GDP-1 GeneSeq Accession WO9406449 Members of the TGF-beta family of The effect of GDF-1 on signaling can Developmental R60961 proteins initiate cell signaling by be assayed by treating Primary disorders, Induction of binding to heteromeric receptor BAECs transferred with a construct Cartilage, Tissue and complexes of type I (TbetaRI) and called p3TP-Lux, containing a TGF- Bone Growth, and type II (TbetaRII) serine/threonine beta responsive promoter fused to a Diabetes kinase receptors (reviewed by reporter gene, and measuring Massague, J. et al. (1994) Trends Cell luciferase gene expression (Wrana et Biol. 4: 172 178; Miyazono, K. et al. al., 1994, Nature 370: 341-347). (1994) Adv. Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg, R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341 347). BMP-9 GeneSeq Accession WO9533830 BMP-9 belongs to the transforming BMP-9 activity can be determined Induction of Cartilage, R86903 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-10 GeneSeq Accession WO9426893 BMP-10 belongs to the transforming BMP-10 activity can be determined Induction of Cartilage, R66202 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-12 GeneSeq Accession WO9516035 BMP-12 belongs to the transforming BMP-12 activity can be determined Induction of Cartilage, R78734 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-15 GeneSeq Accession W09636710 BMP-15 belongs to the transforming BMP-15 activity can be determined Induction of Cartilage, W11261 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-17 GeneSeq Accession WO9929718 BMP-17 belongs to the transforming BMP-17 activity can be determined Induction of Cartilage, Y17870 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-18 GeneSeq Accession WO9929718 BMP-18 belongs to the transforming BMP-18 activity can be determined Induction of Cartilage, Y17871 growth factor-beta (TGFB) superfamily. using the following assays known in Tissue and Bone Bone morphogenic protein induces bone the art: Nat Genet. 2001 January; Growth, and Diabetes formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Inhibin alpha GeneSeq Accession WO0020591 The inhibin beta A subunit joins the Tumor suppressor activity of inhibin Tumor suppression. B02806 alpha subunit to form a pituitary FSH can be determined using assays secretion inhibitor. Inhibin has been known in the art: Matzuk et al., shown to regulate gonadal stromal cell Nature 1992 Nov. 26: 360 (6402); proliferation negatively and to have 313-9. tumour-suppressor activity. In addition, serum levels of inhibin have been shown to reflect the size of granulosa-cell tumors and can therefore be used as a marker for primary as well as recurrent disease. Inhibin beta GeneSeq Accession WO0020591 The inhibin beta A subunit joins the Tumor suppressor activity of inhibin Tumor suppression. H02808 alpha subunit to form a pituitary FSH can be determined using assays secretion inhibitor. Inhibin has been known in the art: Matzuk et al., shown to regulate gonadal stromal cell Nature 1992 Nov. 26: 360 (6402); proliferation negatively and to have 313-9. tumour-suppressor activity. In addition, serum levels of inhibin have been shown to reflect the size of granulosa-cell tumors and can therefore be used as a marker for primary as well as recurrent disease. Cerebus Protein GeneSeq Accession WO9849296 Cerebus is believed to be involved in the BMP activity, in the presence of the BMP Antagonist useful W86032 inhibition of BMP activity antagonist Cerebus, can be for Osteosarcoma, determined using the following abnormal bone growth. assays known in the art: Nat Genet. 2001 January; 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Soluble BMP GeneSeq Accession WO9614579 Soluble BMP receptor kinase protein-3 BMP activity, in the presence of the BMP Antagonist useful Receptor Kinase R95227 is involved in the binding of BMPs. soluble antagonist BMP receptor for Osteosarcoma, Protein-3 Soluble BMP receptor kinase protein-3 kinase protein-3, can be determined abnormal bone growth. is useful as an antagonist for the using the following assays known in inhibition of BMP activity. the art: Nat Genet. 2001 January; 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP Processing GeneSeq Accession WO9741250 BMPs belong to the transforming BMP activity, in the presence of the Bone formation or Enzyme Furin W36099 growth factor-beta (TGFB) superfamily. Furin, can be determined using the Regeneration Bone morphogenic protein induces bone following assays known in the art: Abnormalities formation. Nat Genet. 2001 January; 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. TGF-beta 1 GeneSeq Accession WO9216228 Members of the TGF-beta family of The effect of TGF betas on signaling Useful for treating R29657 proteins initiate cell signaling by can be assayed by treating Primary cancer and to promote binding to heteromeric receptor BAECs transfected with a construct wound healing. complexes of type I (TbetaRI) and type called p3TP-Lux, containing a TGF- II (TbetaRII) serine/threonine kinase beta responsive promoter fused to a receptors (reviewed by Massague, J. et reporter gene, and measuring al. (1994) Trends Cell Biol. 4: 172 178; luciferase gene expression (Wrana et Miyazono, K. et al. (1994) Adv. al., 1994, Nature 370: 341-347). Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. TGF-beta 2 GeneSeq Accession EP542679 Members of the TGF-beta family of The effect of TGF betas on signaling Useful for treating R39659 proteins initiate cell signaling by can be assayed by treating Primary cancer and to promote binding to heteromeric receptor BAECs transfected with a construct wound healing. complexes of type I (TbetaRI) and type called p3TP-Lux, containing a TGF- II (TbetaRII) serine/threonine kinase beta responsive promoter fused to a receptors (reviewed by Massague, J. et reporter gene, and measuring al. (1994) Trends Cell Biol. 4: 172 178; luciferase gene expression (Wrana et Miyazono, K. et al. (1994) Adv. al., 1994, Nature 370: 341-347). Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. ZTGF-beta 9 GeneSeq Accession WO0015798 Members of the TGF-beta family of The effect of TGF betas on signaling Useful for treating Y70654 proteins initiate cell signaling by can be assayed by treating Primary cancer and to promote binding to heteromeric receptor BAECs transfected with a construct wound healing. complexes of type I (TbetaRI) and type called p3TP-Lux, containing a TGF- II (TbetaRII) serine/threonine kinase beta responsive promoter fused to a receptors (reviewed by Massague, J. et reporter gene, and measuring al. (1994) Trends Cell Biol. 4: 172 178; luciferase gene expression (Wrana et Miyazono, K. et al. (1994) Adv. al., 1994, Nature 370: 341-347). Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. Anti-TGF beta GB2305921 Members of the TGF-beta family of The effect of TGF betas on signaling Useful for control of family antibodies proteins initiate cell signaling by in the presence of an anti-TGF beta fibrosis, immune, and binding to heteromeric receptor antibody, can be assayed by treating inflammatory disease. complexes of type I (TbetaRI) and type Primary BAECs transfected with a II (TbetaRII) serine/threonine kinase construct called p3TP-Lux, receptors (reviewed by Massague, J. et containing a TGF-beta responsive al. (1994) Trends Cell Biol. 4: 172 178; promoter fused to a reporter gene, and Miyazono, K. et al. (1994) Adv. measuring luciferase gene expression Immunol. 55: 181-220). Activation of (Wrana et al., 1994, Nature 370: 341-347). this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. Latent TGF beta GeneSeq Accession WO0012551 Members of the TGF-beta family of The effect of TGF betas on signaling Useful for inhibiting binding protein II Y70552 proteins initiate cell signaling by in the presence of a TGF beta binding tissue or tumor growth. binding to heteromeric receptor protein, can be assayed by treating complexes of type I (TbetaRI) and type Primary BAECs transfected with a II (TbetaRII) serine/threonine kinase construct called p3TP-Lux, receptors (reviewed by Massague, J. et containing a TGF-beta responsive al. (1994) Trends Cell Biol. 4: 172 178; promoter fused to a reporter gene, and Miyazono, K. et al. (1994) Adv. measuring luciferase gene expression Immunol. 55: 181-220). Activation of (Wrana et al., 1994, Nature 370: 341-347). this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. MP52 GeneSeq Accession WO9741250 Members of the TGF-beta family of The effect of TGF betas on signaling Bone formation or W36100 proteins initiate cell signaling by can be assayed by treating Primary Regeneration binding to heteromeric receptor BAECs transfected with a construct Abnormalities complexes of type I (TbetaRI) and type called p3TP-Lux, containing a TGF- II (TbetaRII) serine/threonine kinase beta responsive promoter fused to a receptors (reviewed by Massague, J. et reporter gene, and measuring al. (1994) Trends Cell Biol. 4: 172 178; luciferase gene expression (Wrana et Miyazono, K. et al. (1994) Adv. al., 1994, Nature 370: 341-347). Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. b57 Protein GeneSeq Accession WO9837195 BMPs are involved in the induction of BMP activity, in the presence of b57 BMP Antagonist useful W69293 bone formation. Specific antagonists are protein, can be determined using the for Osteosarcoma, useful is preventing this activity from following assays known in the art: abnormal bone growth. occurring. Nat Genet. 2001 January; 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 1089-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Deve. 10, 1580-1594. Resistin GeneSeq Accession WO0064920 This gcne belongs to the family defined Ability of resistin to influence type Type II diabetes and W69293 by mouse FIZZI and FIZZ3/Resistin II diabetes can be determined using Syndrome X. genes. The characteristic feature of this assays known in the art: Pontoglio et family is the C-terminal stretch of 10 cys al., J Clin Invest 1998 May 15; residues with identical spacing. The 101(10): 2215-22. mouse homolog of this protein is secreted by adipocytes, may be the hormone potantially linking obesity to type II diabetes. Galectin-4 GeneSeq Accession WO9703190 Galectins are a family of carbohydrate- Ability of Galectin-4 polypeptides to Lactose intolerance. W11841 binding proteins characterized by an bind lactose can be determined using affinity for beta-galactoside containing assays known in the art: Wada, et al., glycoconjugates. J Biol Chem 1997 Feb. 28; 272(9): 6078-86. APM-I; ACRP-30; GeneSeq Accession W00026363 ACPR30 gene is exclusively expressed in Ability of ACRP30 polypeptides to Obesity, Metabolic Famoxin Y71035 adipose tissue. ACRP30 is thought to influence obesity and fat oxidation disorders, Lipid increase fatty acid oxidation by muscle can be determined using assays Metabolism; Hormone tissue. known in the art: Fruebis et al., Proc Secretion. Nat'l Acad Sci USA 2001 Feb. 13; 98(4): 2005-10. ACRP-30 GeneSeq Accession WO0063376 ACPR30 gene is exclusively expressed in Ability of ACRP30 homologue Obesity, Metabolic Homologue; B30234 adipose tissue. ACRP30 is thought to polypeptides to influence obesity disorders, Lipid Complement increase fatty acid oxidation by muscle and fat oxidation can be determined Metabolism; Hormone Component Clq C tissue. using assays known in the art: Secretion. Fruebis et al., Proc Nat'l Acad Sci USA 2001 Feb. 13; 98(4): 2005-10. Calpain-10a GeneSeq Accession WO0023603 Calpain is believed to play a role in Ability of Calpain-10 to influence Diabetes mellitus; Y79567 insulin secretion and insulin activity, and type II diabetes can be determined Regulation of Insulin therefore may be useful in the treatment using assays known in the art: secretory response; of type II diabetes. Pontoglio et al., J Clin Invest 1998 Insulin mediated May 15; 101(10): 2215-22. glucose transport disorders. Calpain-10b GeneSeq Accession WO0023603 Calpain is believed to play a role in Ability of Calpain-10 to influence Diabetes mellitus; Y79568 insulin secretion and insulin activity, and type II diabetes can be determined Regulation of Insulin therefore may be useful in the treatment using assays known in the art: secretory response; of type II diabetes. Pontoglio et al., J Clin Invest 1998 Insulin mediated May 15; 101(10): 2215-22. glucose transport disorders. Calpain-10c GeneSeq Accession WO0023603 Calpain is believed to play a role in Ability of Calpain-10 to influence Diabetes mellitus; Y79569 insulin secretion and insulin activity, and type II diabetes can be determined Regulation of Insulin therefore may be useful in the treatment using assays known in the art: secretory response; of type II diabetes. Pontoglio et al., J Clin Invest 1998 Insulin mediated May 15; 101(10): 2215-22. glucose transport disorders PDGF-D GeneSeq Accession WO0027879 Vascular Endothelial Growth Factor. Proliferation assay using NR6R-3T3 Wound Healing; Y71130 cells (Rizzino 1988 Cancer Res. 48: Atherosclermis. 4266). FasL GeneSeq Accession WO9936079 Activities associated with apoptosis and Activity can be determined using Apoptosis-related Y28594 immune system functions. Apoptosis assays known in the art: disorders; Autoimmune Walczak et al. (1996) EMBOJ 16: disorders; Graft v-Host 5386-5397. disorders. Chondro modulin- GeneSeq Accession W00029579 Chondromodulin proteins are cartilage Ability of Chondromodulin-like Antianglogenic agent; like protein Y71262 proteins thought to confer resistance to protein to inhibit vascularization can Osteoblast proliferation anglogeneis, and thus are useful as anti- be determined using assays known stimulator; prevents angiogenic agents that may have utility in in the art: Hirakie et al., J Biol Chem vascularization of combating cancer. 1997 Dec. 19; 272(51): 32419-26. cartilage tissue; Useful to treat cancer. Patched GeneSeq Accession U.S. Pat. No. 5837538 Patched is a tumour-suppressor receptor Ability of soluble Patched to bind to Receptor for Hedgehog W72969 for Sonic hedgehog (shh), which is a and inhibit the activities of shh can cellular proliferation protein that controls developmental be determined using assays known signaling molecule. patterning and growth. in the art: Stone et al., Nature 1996 This receptor is useful Nov. 14; 384(6605): 129-34. as a means of preventing cellular proliferation via the shh signaling pathway, thus useful for cancers. Patched-2 GeneSeq Accession WO9953058 Patched is a tumour-suppressor receptor Ability of soluble Patched to bind to Receptor for Hedgehog Y43261 for Sonic hedgehog (shh), which is a and inhibit the activities of shh can cellular proliferation protein that controls developmental be determined using assays known signaling molecule. patterning and growth. in the art: Stone et al., Nature 1996 This receptor is useful Nov. 14; 384(6605): 129-34. as a means of preventing cellular proliferation via the shh signaling pathway, thus useful for cancers. Maspin; Protease GeneSeq Accession WO9405804 Maspin is a member of the serpin family The inhibitory effects of Maspin and Tumor suppressor which Inhibitor 5 R50938 of serine protease inhibitors that is other protease inhibitors can be is down-regulated in thought to suppress tumor metastasis. assayed using methods known in the breast cancers. The art such as a labeled protease maspin protein has substrate, for example, Universal tumour suppressing and Protease Substrate (casein, resorufin- invasion suppressing labeled): Roche Molecular activity. Biochemicals, Cat. No. 1080733. Endostatin GeneSeq Accession WO0064946 Endostatin is believed to inhibit effects of The inhibitory effects of endostatin Anti-angiogenic activity. B28399 capillary endothelial cell proliferation. can be assayed using assays Useful in the prevention disclosed by Cao et al. (1996) J. and/or treatment of Biol. Chem. 271 29461-29467. cancers. aFGF; FGF-1 GeneSeq Accession EP298723 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and P94037 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, 4266); Examples 23 and 39 such as epithelial cells disclosed herein, and keratinocytes. Antagonists may be useful as anti-cancer agents. bFGF; FGF-2 GeneSeq Accession FR2642086 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and R06685 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, 4266); Examples 23 and 39 such as epithelial cells disclosed herein. and keratinocytes. Antagonists may be useful as anti-cancer agents. FGF-3; INT-2 GeneSeq Accession WO9503831 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and R07824 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, 4266); Examples 23 and 39 such as epithelial cells disclosed herein. and keratinocytes. Antagonists may he useful as anti-cancer agents. FGF-4; HST-1; GeneSeq Accession WO9503831 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and HBGF-4 R07825 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, 4266); Examples 23 and 39 such as epithelial cells disclosed herein. and keratinocytes. Antagonists may be useful as anti-cancer agents. FGF-5 GeneSeq Accession WO9730155 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and W22600 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, 4266); Examples 23 and 39 such as epithelial cells disclosed herein. and keratinocytes. Antagonists may be useful as anti-cancer agents. FGF-6; Heparin GeneSeq Accession EP613946 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and binding secreted R58555 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, transforming 4266); Examples 23 and 39 such as epithelial cells factor-2 disclosed herein. and keratinocytes. Antagonists may be useful as anti-cancer agents. FGF-8 GeneSeq Accession WO9524928 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and R80783 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, 4266); Examples 23 and 39 such as epithelial cells disclosed herein. and keratinocytes. Antagonists may be useful as anti-cancer agents. FGF-9; Gila GeneSeq Accession WO9503831 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and activating factor R70822 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, 4266); Examples 23 and 39 such as epithelial cells disclosed herein. and keratinocytes. Antagonists may be useful as anti-cancer agents. FGF-12; Fibroblast GeneSeq Accession WO9635708 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and growth factor W06309 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, homologous 4266); Examples 23 and 39 such as epithelial cells factor-1 disclosed herein. and keratinocytes. Antagonists may be useful as anti-cancer agents. FGF-15 GeneSeq Accession WO9927100 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and Y08582 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, 4266); Examples 23 and 39 such as epithelial cells disclosed herein. and keratinocytes. Antagonists may be useful as anti-cancer agents. FGF-16 GeneSeq Accession WO9918128 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and Y05474 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, 4266); Examples 23 and 39 such as epithelial cells disclosed herein. and keratinocytes. Antagonists may be useful as anti-cancer agents. FGF-18 GeneSeq Accession WO9927100 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of growth and Y08590 cells (Rizzino 1988 Cancer Res. 48: proliferation of cells, 4266); Examples 23 and 39 such as epithelial cells disclosed herein. and keratinocytes. Antagonists may be useful as anti-cancer agents. fit-3 ligand GeneSeq Accession EP627487 Stem Cell Progenitor Chemokine activities can be Promotion of immune R67541 determined using assays known in cell growth and/or the art: Methods in Molecular differentiation. Biology, 2000, vol. 138: Chemokine Protocols. Edited by: A. E. I. Proudfoot, T. N. C. Wells, and C. A. Power.  ©Humana Press Inc., Totowa, NJ VEGF-110 GeneSeq Accession WO0013702 Promotes the growth and/or proliferation VEGF activity can be determined Promotion of growth and Y69417 of endothelial cells. using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGB-121 GeneSeq Accession WO0071713 Promotes the growth and/or proliferation VEGF activity can be determined Promotion of growth and B50432 of endothelial cells. using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-138 GeneSeq Accession WO9940197 Promotes the growth and/or proliferation VEGF activity can be determined Promotion of growth and Y43483 of endothelial cells. using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-145 GeneSeq Accession WO0013702 Promotes the growth and/or proliferation VEGF activity can be determined Promotion of growth and Y69413 of endothelial cells. using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-162 GeneSeq Accession W09940197 Promotes the growth and/or proliferation VEGF activity can be determined Promotion of growth and Y43484 of endothelial cells. using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-165 GeneSeq Accession WO0013702 Promotes the growth and/or proliferation VEGF activity can be determined Promotion of growth and Y69414 of endothelial cells. using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-182 GeneSeq Accession W09940197 Promotes the growth and/or proliferation VEGF activity can be determined Promotion of growth and Y43483 of endothelial cells. using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-189 GeneSeq Accession WO0013702 Promotes the growth and/or proliferation VEGF activity can be determined Promotion of growth and Y69415 of endothelial cells. using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-206 GeneSeq Accession W00013702 Promotes the growth and/or proliferation VEGF activity can be determined Promotion of growth and Y69416 of endothelial cells. using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-D GeneSeq Accession WO9807832 Promotes the growth and/or proliferation VEGF activity can be determined Promotion of growth and W53240 of endothelial cells. using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-E; VEGF-X GeneSeq Accession W09947677 Promotes the growth and/or proliferation VEGF activity can be determined Promotion of growth and Y33679 of endothelial cells. using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF Receptor; GeneSeq Accession WO9831794 Receptor for VEGF polypeptides VEGF activity, in the presence of VEGF Receptor. Fusion KDR; flk-1 W69679 flk-1 polypeptides, can be protein with the determined using assays known in extracellular domain is the art, such as those disclosed in useful as an anti- International Publication No. angiogenic agent. WO0045835, for example. Antagonists may be useful in the promotion of angiogenesis. Soluble VEGF GeneSeq Accession U.S. Pat. No. 5,712,380 Receptor for VEGF polypeptides VEGF activity, in the presence of VEGF Receptor. Fusion Receptor W47037 VEGF Receptor polypeptides, can protein with the be determined using assays known extracellular domain is in the art, such as those disclosed in useful as an anti- International Publication No. angiogenic agent. WO0045835, for example. Antagonists may be useful in the promotion of angiogenesis. flt-1 GeneSeq Accession WO0021560 Receptor for VEGF polypeptides VEGF activity, in the presence of VEGF Receptor. Fusion Y70751 flt-1 polypeptides, can be protein with the determined using assays known in extracellular domain is the art, such as those disclosed in useful as an anti- International Publication No. angiogenic agent. WO0045835, for example. Antagonists may be useful in the promotion of angiogenesis. VEGF R-3; flt-4 GeneSeq Accession WO0058511 Receptor for VEGF polypeptides VEGF activity, in the presence of VEGF Receptor. Fusion B29047 flt-4 polypeptides, can be protein with the determined using assays known in extracellular domain is the art, such as those disclosed in useful as an anti- International Publication No. angiogenic agent. WO0045835, for example. Antagonists may be useful in the promotion of angiogenesis. Neuropilin-1 GeneSeq Accession WO9929858 Vascular Endothelial Growth Factor VEGF activity can be determined Promotion of growth and Y06319 using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Neuropilin-2 GeneSeq Accession WO9929858 Vascular Endothelial Growth Factor VEGF activity can be determined Promotion of growth and Y03618 using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Human fast twitch GeneSeq Accession W09730085 Troponins are contractile proteins that are Ability of soluble Troponins to Anti-angiogenesis skeletal muscle W22597 thought to inhibit angiogenesis. High inhibit anglogenesis can be troponin C levels may contribute to the difficulty determined using assays known in encountered in revascularizing the the art:. Proc Natl Acad Sci USA ischemic myocardium after 1999 Mar. 16; 96(6): 2645-50. cardiovascular injury. Human fast twitch GeneSeq Accession W09730085 Troponins are contractile proteins that are Ability of soluble Troponins to Anti-angiogenesis skeletal muscle W18054 thought to inhibit angiogenesis. High inhibit anglogenesis can be troponin I levels may contribute to the difficulty determined using assays known in encountered in revascularizing the the art:. Proc Natl Acad Sci USA ischemic myocardium after 1999 Mar. 16; 96(6): 2645-50. cardiovascular injury. Human fast twitch GeneSeq Accession W09730085 Troponins are contractile proteins that are Ability of soluble Troponins to Anti-angiogenesis skeletal muscle W22599 thought to inhibit angiogenesis. High inhibit anglogenesis can be troponin T levels may contribute to the difficulty determined using assays known in encountered in revascularizing the the art:. Proc Natl Acad Sci USA ischemic myocardium after 1999 Mar. 16; 96(6): 2645-50. cardiovascular injury. fragment. GeneSeq Accession W09719955 Troponins are contractile proteins that are Ability of soluble Troponins to Anti-angiogenesis myofibrillar W18053 thought to inhibit angiogenesis. High inhibit anglogenesis can be protein troponin I levels may contribute to the difficulty determined using assays known in encountered in revascularizing the the art:. Proc Natl Acad Sci USA ischemic myocardium after 1999 Mar. 16; 96(6): 2645-50. cardiovascular injury. myofibrillar GeneSeq Accession W09719955 Troponins are contractile proteins that are Ability of soluble Troponins to Anti-angiogenesis protein troponin I W18054 thought to inhibit angiogencsis. High inhibit anglogenesis can be levels may contribute to the difficulty determined using assays known in encountered in revascularizing the the art:. Proc Natl Acad Sci USA ischemic myocardium after 1999 Mar. 16; 96(6): 2645-50. cardiovascular injury. Troponin peptides GeneSeq Accessions WO9933874 Troponins are contractile proteins that are Ability of soluble Troponins to Anti-angiogenesis Y29581, Y29582, thought to inhibit angiogencsis. High inhibit anglogenesis can be Y29583, Y29584, levels may contribute to the difficulty determined using assays known in Y29585, and encountered in revascularizing the the art:. Proc Natl Acad Sci USA Y29586 ischemic myocardium after 1999 Mar. 16; 96(6): 2645-50. cardiovascular injury. Human fast twitch GeneSeq Accession WO0054770 Troponins are contractile proteins that are Ability of soluble Troponins to Anti-angiogenesis skeletal muscle B00134 thought to inhibit angiogencsis. High inhibit anglogenesis can be Troponin subunit C levels may contribute to the difficulty determined using assays known in encountered in revascularizing the the art:. Proc Natl Acad Sci USA ischemic myocardium after 1999 Mar. 16; 96(6): 2645-50. cardiovascular injury. Human fast twitch GeneSeq Accession WO0054770 Troponins are contractile proteins that are Ability of soluble Troponins to Anti-angiogenesis skeletal muscle B00135 thought to inhibit angiogencsis. High inhibit anglogenesis can be Troponin subunit I levels may contribute to the difficulty determined using assays known in Protein encountered in revascularizing the the art:. Proc Natl Acad Sci USA ischemic myocardium after 1999 Mar. 16; 96(6): 2645-50. cardiovascular injury. Human fast twitch GeneSeq Accession WO0054770 Troponins are contractile proteins that are Ability of soluble Troponins to Anti-angiogenesis skeletal muscle B00136 thought to inhibit angiogencsis. High inhibit anglogenesis can be Troponin subunit T levels may contribute to the difficulty determined using assays known in encountered in revascularizing the the art:. Proc Natl Acad Sci USA ischemic myocardium after 1999 Mar. 16; 96(6): 2645-50. cardiovascular injury. Activator GeneSeq Accession WO9013648 PAIs are believed to play a role in cancer, Methods that measure plasminogen Anti-angiogenesis; Inbibitor-1; PAI-1 R08411 and cardiovascular disease and blood- activator inhibitor (PAI) activity are blood-clotting disorders. clotting disorders. known in the art, for example, assay the ability of PAI to inhibit tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep. 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti-angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar. 16; 96(6): 2645-50. Plasminogen GeneSeq Accession DE3722673 PAIs are believed to play a role in cancer, Methods that measure plasminogen Anti-angiogenesis; Activator P94160 and cardiovascular disease and blood- activator inhibitor (PAI) activity are blood-clotting disorders. Inhibitor-2; PAI-2 clotting disorders. known in the art, for example, assay the ability of PAI to inhibit tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep. 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti-angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar. 16; 96(6): 2645-50. Activator GeneSeq Accession WO9102057 PAIs are believed to play a role in cancer, Methods that measure plasminogen Anti-angiogenesis; Inhibitor-2; PAI-2 R10921 and cardiovascular disease and blood- activator inhibitor (PAI) activity are blood-clotting disorders. clotting disorders. known in the art, for example, assay the ability of PAI to inhibit tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep. 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti-angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar. 16; 96(6): 2645-50. Human PAI-1 GeneSeq Accessions WO9105048 PAIs are believed to play a role in cancer, Methods that measure plasminogen Anti-angiogenesis; mutants R11755, R11756, and cardiovascular disease and blood- activator inhibitor (PAI) activity are blood-clotting disorders. R11757, R11758, clotting disorders. known in the art, for example, assay R11759, R11760, the ability of PAI to inhibit tissue R11761, R11762 plasminogen activator (tPA) or and R11763 urokinase (uPA): J Biochem Biophys Methods 2000 Sep. 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti-angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar. 16; 96(6): 2645-50. CXCR3; CXC GeneSeq Accession WO0018431 Chemokines are a family of related small, Chemokine activities can be Soluble CXCR3 Y79372 secreted proteins involved in biological determined using assays known in polypeptides may be processes ranging from hematopoiesis, the art: Methods in Molecular useful for inhibiting angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine chemokine activities and Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, viral infection. similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Modified Rantes GeneSeq Accession WO9737005 Chemokines are a family of related small, Chemokine activities can be Immune disorders. W38129 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES GeneSeq Accession EP905240 Chemokines are a family of related small, Chemokine activities can be Immune disorders. Y05299 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCI-la GeneSeq Accession WO9509232 Chemokines are a family of related small, Chemokine activities can be Immune disorders. R73914 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis; and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-lb GeneSeq Accession WO9929728 Chemokines are a family of related small, Chemokine activities can be Immune disorders. Y26176 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-I receptor GeneSeq Accession WO9519436 Chemokines are a family of related small, Chemokine activities can be Soluble MCP-1 Receptor R79165 secreted proteins involved in biological determined using assays known in polypeptides may be processes ranging from hematopoiesis, the art: Methods in Molecular useful for inhibiting angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine chemokine activities and Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, viral infection. similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-3 GeneSeq Accession W09509232 Chemokines are a family of related small, Chemokine activities can be Immune disorders. R73915 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-4 receptor GeneSeq Accession W09809171 Chemokines are a family of related small, Chemokine activities can be Soluble MCP-4 Receptor W56689 secreted proteins involved in biological determined using assays known in polypeptides may be processes ranging from hematopoiesis, the art: Methods in Molecular useful for inhibiting angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine chemokine activities and Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, viral infection. similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES receptor GeneSeq Accession U.S. Pat. No. 5,652,133 Chemokines are a family of related small, Chemokine activities can be Soluble RANTES W29588 secreted proteins involved in biological determined using assays known in Receptor polypeptides processes ranging from hematopoiesis, the art: Methods in Molecular may be useful for angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine inhibiting chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, activities and viral similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. infection. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CCR5 variant GeneSeq Accession WO9854317 Chemokines are a family of related small, Chemokine activities can be Soluble CCR5 W88238 secreted proteins involved in biological determined using assays known in polypeptides may be processes ranging from hematopoiesis, the art: Methods in Molecular useful for inhibiting angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine chemokine activities and Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, viral infection. similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CCR7 GeneSeq Accession U.S. Pat. No. 6,153,441 Chemokines are a family of related small, Chemokine activities can be Soluble CCR7 B50859 secreted proteins involved in biological determined using assays known in polypeptides may be processes ranging from hematopoiesis, the art: Methods in Molecular useful for inhibiting angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine chemokine activities and Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, viral infection. similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CXC3 GeneSeq Accession WO9727299 Chemokines are a family of related small, Chemokine activities can be Immune disorders. W23345 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Eotaxin GeneSeq Accession WO9700960 Chemokines are a family of related small, Chemokine activities can be Immune disorders. W10099 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Neurotactin GeneSeq Accessions U.S. Pat. No. 6,013,257 Neurotactin may play a role in Chemotactic leukocyte migration Immune disorders. Y77537, W34307, WO9742224 chemotactic leukocyte migration and assays are known in the art, for Y53259, and, brain inflammation processes. example: J. Immunol. Methods 33, Y77539 ((1980)); Nature 1997 Jun. 5; 387(6633): 611-7. Human CKbeta-9 GeneSeq Accession U.S. Pat. No. 6,153,441 Chemokines are a family of related small, Chemokine activities can be Immune disorders. B50860 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Lymphotactin GeneSeq Accession WO0073320 Chemokines are a family of related small, Chemokine activities can be Immune disorders. B50052 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G. MIP-3 alpha GeneSeq Accession WO9801557 Chemokines are a family of related small, Chemokine activities can be Immune disorders. W44398 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G. MIP-3 beta GeneSeq Accession WO9801557 Chemokines are a family of related small, Chemokine activities can be Immune disorders. W44399 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G. MIP-Gamma GeneSeq Accession WO9504158 Chemokines are a family of related small, Chemokine activities can be Immune disorders. R70798 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G. Stem Cell GeneSeq Accession WO9104274 Chemokines are a family of related small, Chemokine activities can be Hematopoietic growth Inhibitory R11553 secreted proteins involved in biological determined using assays known in factors. Factor processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G. thrombopoietin GeneSeq Accession WO9521920 Thrombopoietin is involved in the Thrombopoietin (TPO) can be Hematopoietic growth R79905 regulation of the growth and assayed to determine regulation of factors. differentiation of megakaryocytes and growth and differentiation of preceptors thereof. megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1): 51-8 and within. c-kit ligand; GeneSeq Accession EP992579 and C-kit ligan is thought to stimulate the Chemokine activities can be Hematopoietic growth SCF; Mast cell Y53284, R83978 EP676470 proliferation of mast cells, and is able to determined using assays known in factors. growth factor; and R83977 augment the proliferation of both the art: Methods in Molecular MGF; myeloid and lymphoid hematopoietic Biology, 2000, vol. 138: Chemokine Fibrosarcoma- progenitors in bone marrow culture. C- Protocols. Edited by: A. E. I. Proudfoot, derived stem kit ligand is also though to act T. N. C. Wells, and C. A. Power. cell factor synergistically with other cytokines.  ©Humana Press Inc., Totowa, NJ. Platelet derived GeneSeq Accession WO0066736 Vascular Endothelial Growth Factor VEGF activity can be determined Promotion of growth and growth factor B48653 using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Melanoma GeneSeq Accession WO9503328 Melanoma inhibiting protein has Tumor suppressor activity of Cancer; melanoma inhibiting protein R69811 melanoma-inhibiting activity and can be melanoma inhibiting protein can be used to treat cancer (melanoma, determined using assays known in glioblastoma, neuroblastoma, small cell the art: Matzuk et al., Nature 1992 lung cancer, neuroectodermal tumors) or Nov. 26; 360(6402): 313-9. as an immunosuppressant (it inhibits IL-2 or phytohaemagglutinin induced proliferation of peripheral blood lymphocytes. Glioma-derived GeneSeq Accession EP399816 Vascular Endothelial Growth Factor VEGF activity can be determined Promotion of growth and growth factor R08120 using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Platelet derived GeneSeq Accession EP682110 Vascular Endothelial Growth Factor VEGF activity can be determined Promotion of growth and growth factor R84759 using assays known in the art, such proliferation of cells, precursor A as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Platelet derived GeneSeq Accession EP682110 Vascular Endothelial Growth Factor VEGF activity can be determined Promotion of growth and growth factor R84760 using assays known in the art, such proliferation of cells, precursor B as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Platelet derived GeneSeq Accession EP282317 Vascular Endothelial Growth Factor VEGF activity can be determined Promotion of growth and growth factor Bv- P80595 and using assays known in the art, such proliferation of cells, sis P80596 as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Placental Growth GeneSeq Accessions WO9206194 Vascular Endothelial Growth Factor VEGF activity can be determined Promotion of growth and Factor R23059 and using assays known in the art, such proliferation of cells, R23060 as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Placental Growth GeneSeq Accession DE19748734 Vascular Endothelial Growth Factor VEGF activity can be determined Promotion of growth and Factor-2 Y08289 using assays known in the art, such proliferation of cells, as those disclosed in International such as vascular Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Thrombopoietin GeneSeq Accession WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be Thrombocytopenia, derivative1 Y77244 regulation of the growth and assayed to determine regulation of cancer. differentiation of megakaryocytes and growth and differentiation of preceptors thereof. megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1): 51-8 and within. Thrombopoietin GeneSeq Accession WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be Thrombocytopenia, derivative2 Y77255 regulation of the growth and assayed to determine regulation of cancer. differentiation of megakaryocytes and growth and differentiation of preceptors thereof. megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1): 51-8 and within. Thrombopoietin GeneSeq Accession WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be Thrombocytopenia, derivative3 Y77262 regulation of the growth and assayed to determine regulation of cancer. differentiation of megakaryocytes and growth and differentiation of preceptors thereof. megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1): 51-8 and within. Thrombopoietin GeneSeq Accession WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be Thrombocytopenia, derivative4 Y77267 regulation of the growth and assayed to determine regulation of cancer. differentiation of megakaryocytes and growth and differentiation of preceptors thereof. megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1): 51-8 and within. Thrombopoietin GeneSeq Accession WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be Thrombocytopenia, derivative5 Y77246 regulation of the growth and assayed to determine regulation of cancer. differentiation of megakaryocytes and growth and differentiation of preceptors thereof. megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1): 51-8 and within. Thrombopoietin GeneSeq Accession WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be Thrombocytopenia, derivative6 Y77253 regulation of the growth and assayed to determine regulation of cancer. differentiation of megakaryocytes and growth and differentiation of preceptors thereof. megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1): 51-8 and within. Thrombopoietin GeneSeq Accession WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be Thrombocytopenia, derivative7 Y77256 regulation of the growth and assayed to determine regulation of cancer. differentiation of megakaryocytes and growth and differentiation of preceptors thereof. megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1): 51-8 and within. Fractalkine GeneSeq Accession U.S. Pat. No. 6,043,086 Fractalkine is believed to play a role in Fractalkine activity can be Immune disorders. Y53255 chemotactic leukocyte migration and determined using Chemotactic neurological disorders. leukocyte migration assays known in the art, for example: J. Immunol. Methods 33, ((1980)); Nature 1997 Jun 5; 387(6633): 611-7. CXC3 GeneSeq Accession WO9757599 Chemokines are a family of related small, Chemokine activities can be Immune disorders. W23345 secreted proteins involved in biological determined using assays known in processes ranging from hematopoiesis, the art: Methods in Molecular angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine Members of this family are involved in a Prototols. Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CCR7 GeneSeq Accession U.S. Pat. No. 6,153,441 Chemokines are a family of related small, Chemokine activities can be Soluble CCR7 B50859 secreted proteins involved in biological determined using assays known in polypeptides may be processes ranging from hematopoiesis, the art: Methods in Molecular useful for inhibiting angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine chemokine activities and Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, viral infection. similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Nerve Growth GeneSeq Accession EP414151 Nerve Growth Factor Proliferation assay using NR6R-3T3 Neurological disorders, Factor-beta R11474 cells (Rizzino 1988 Cancer Res. 48: cancer 4266) Nerve Growth GeneSeq Accession EP859056 Nerve Growth Factor Proliferation assay using NR6R 3T3 Neurological disorders, Factor-beta2 W69725 cells (Rizzino 1988 Cancer Res. 48: cancer 4266 Neurotrophin-3 GeneSeq Accession WO9821234 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, W8889 survival and synaptic plasticity. known in the art can be used to assay cancer for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar. 13; 98(6): 3555-3560. Neurotrophin-3 GeneSeq Accession WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, R47100 survival and synaptic plasticity. known in the art can be used to assay cancer for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar. 13; 98(6): 3555-3560. Neurotrophin-4a GeneSeq Accession WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, R47101 survival and synaptic plasticity. known in the art can be used to assay cancer for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar. 13; 98(6): 3555-3560. 13; 98(6): 3555-3560 Neurotrophin-4b GeneSeq Accession WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, R47102 survival and synaptic plasticity. known in the art can be used to assay cancer tyrosine kinases. for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar. 13; 98(6): 3555-3560. Neurotrophin-4c GeneSeq Accession WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, R47103 survival and synaptic plasticity. known in the art can be used to assay cancer tyrosine kinases. for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar. 13; 98(6): 3555-3560. Neurotrophin-4d GeneSeq Accession WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological disorders, R47102 survival and synaptic plasticity. known in the art can be used to assay cancer tyrosine kinases. for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar. 13; 98(6): 3555-3560. Platelet-Derived GeneSeq Accession U.S. Pat. No. 5,219,739 Vascular Endothelial Growth Factor VEGF activity can be determined Promotion of growth and Growth Factor R38918 using assays known in the art, such as proliferation of cells, A chain those disclosed in International such as vascular Publication No. W00045835, for endothelial cells. example. Hematopoietic and immune disorders. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer Platelet-Derived GeneSeq Accession U.S. Pat. No. 5,219,739 Vascular Endothelial Growth Factor VEGF activity can be determined Promotion of growth and Growth Factor R38919 using assays known in the art, such as proliferation of cells, B chain those disclosed in International such as vascular Publication No. W00045835, for endothelial cells. example. Hematopoietic and immune disorders. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer Stromal Derived GeneSeq Accession WO9948528 Stromal Growth Factor Proliferation assay using NR6R-3T3 Hematopoietic, immune Factor-1 alpha Y39995 cells (Rizzino 1988 Cancer Res. 48: disorders, cancer 4266) Stromal Derived GeneSeq Accession CA2117953 Stromal Growth Factor Proliferation assay using NR6R-3T3 Hematopoietic, immune Factor-1 beta R75420 cells (Rizzino 1988 Cancer Res. 48: disorders, cancer 4266) Tarc GeneSeq Accession WO9711969 Chemotactic for T lymphocytes. May Chemotactic leukocyte migration Antiinflammatory. W14917 play a role in T-cell development. assays are known in the art, for Immune disorders, Thought to bind CCR8 and CCR4 example: J. Immunol. Methods 33 cancer ((1980)) Prolactin GeneSeq Accession WO9521625 Prolactin is involved in immune cell Immune coil proliferation and Reproductive system R78691 proliferation and apoptosis. suppression of apoptosis by prolactin disorders, cancer. can be assayed by methods well- known in the art, for example, Buckley, A R and Buckley D J, Ann NY Acad Sci 2000; 917: 522-33, and within. Prolactin2 GeneSeq Accession U.S. Pat. No. 5,955,346 Prolactin is involved in immune cell Immune coil proliferation and Reproductive system Y31764 proliferation and apoptosis. suppression of apoptosis by prolactin disorders, cancer. can be assayed by methods well- known in the art, for example, Buckley, A R and Buckley D J, Ann NY Acad Sci 2000; 917: 522-33, and within. Follicle GeneSeq Accession EP974359 FSH stimulates secretion of interleukin-1 FSH activities can be determined Reproductive system stimulating Y54160 by cells isolated from women in the using assays known in the art; J Gend disorders, cancer. hormone Alpha follicular phase Specif Med 1999 November-December; 2(6): 30-4; subunit Mol Cell Endocrinol. 1997 Nov. 15; 134(2): 109-18. Follicle GeneSeq Accession EP974359 FSH stimulates secretion of interleukin-1 FSH activities can be determined Reproductive system stimulating Y54161 by cells isolated from women in the using assays known in the art; J Gend disorders, cancer. hormone Beta follicular phase Specif Med 1999 November-December; 2(6): 30-4; subunit Mol Cell Endocrinol. 1997 Nov. 15; 134(2): 109-18. Substance P GeneSeq Accession WO0054053 Substance P is associated with Immuneregulation and bone marrow, diabetes mellitus, (tachykinin) B23027 immunoregulation. cell proliferation by substance P can hypertension, cancer be assayed by methods well-known in the art, for example, Lai et al. Proc Natl Acad Sci USA 2001 Mar. 27; 98(7): 3970-5; Jallat-Daloz et al. Allergy Asthma Proc 2001 January-February; 22(1): 17-23; Kahler et al. Exp Lung Res 2001 January-February; 27(1): 25-46; and Adamus M A and Dabrowski Z J. J Cell Biochem 2001; 81(3)499-506. Ocytocin GeneSeq Accession WO0053755 Oxytocin is involved in the induction of Oxytocin and prostaglandin E(2) inflammatory disorders (Neurophysin I) B24085 and prostaglandin (E2) release as well as an release and Ocytocin (Ca2+) increase immunologic disorders, B24086 increased amount of calcium release by can be assayed by methods well- cancer smooth muscle cells. known in the art, for example, Pavan et al., AM J Obset Gynecol 2000 July; 183(1): 76-82 and Holda et al., Cell Calcium 1996 July; 20(1): 43 51. Vasopressin GeneSeq Accession WO0053755 Vasopressinis believed to have a direct Vasopressin activity can be inflammatory disorders (Neurophysin II) B24085 and antidiuretic action on the kidney, and it is determined using assays known in the immunologic disorders, B24086 thought to cause vasoconstriction of the art, for example, Endocr Regul 1996 cancer peripheral vessels. March; 30(1): 13-17. IL-1 GeneSeq Accession EP165654 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, P60326 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarclio (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. IL-1 mature GeneSeq Accession EP456332 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R14855 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarclio (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. IL-1 beta GeneSeq Accession WO9922763 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, Y08322 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarclio (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. IL-3 variants GeneSeq Accession WO8806161 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, P80382, P80383, multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, P80384, and lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer P80381 macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Kitamura et al (1989) J Cell neutrophils and T lymphocytes, and/or Physiol. 140 323-334. inhibition of interferons. IL-4 GeneSeq Accession WO8702990 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, P70615 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Siegel & Mostowski (1990) J neutrophils and T lymphocytes, and/or Immunol Methods 132, 287-295. inhibition of interferons. IL-4 muteins GeneSeq Accession WO9747744 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, W52151 W52152 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, W52153 W52154 lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer W52155 W52156 macrophages. Known functions include Interferens: A Practical Approach, W52157 W52158 stimulating proliferation of immune cells Clemens et al., eds, IRL Press, W52159 W52160 (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; W52161 W52162 and lymphocytes), chemotaxis of and Siegel & Mostowski (1990) J W52163 W52164 neutrophils and T lymphocytes, and/or Immunol Methods 132, 287-295. and W52165 inhibition of interferons. IL-1 alpha GeneSeq Accession EP324447 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, P90108 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarello (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. IL-3 variants GeneSeq Accession WO9307171 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R38561, R38562, multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, R38563, R38564, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer R38565, R38566, macrophages. Known functions include Interferens: A Practical Approach, R38567, R38568, stimulating proliferation of immune cells Clemens et al.; eds, IRL Press, R38569, R38570, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; R38571, and and lymphocytes), chemotaxis of and Aarden et al (1987) Eur. J. R38572 neutrophils and T lymphocytes, and/or Immunol 17, 1411-16. inhibition of interferons. IL-6 GeneSeq Accession WO9402512 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R45717 and multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, R45718 lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Aarden et al (1987) Eur. J. neutrophils and T lymphocytes, and/or Immunol 17, 1411-16. inhibition of interferons. IL-13 GeneSeq Accession WO9404680 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R48624 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Boutelier et al (1995) J. neutrophils and T lymphocytes, and/or Immunol. Methods 181, 29. inhibition of interferons. IL-4 mutein GeneSeq Accession DE4137333 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R47182 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Siegel & Mostowski (1990) J neutrophils and T lymphocytes, and/or Immunol Methods 132, 287-295. inhibition of interferons. IL-4 mutein GeneSeq Accession DE4137333 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, Y124X R47183 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Siegel & Mostowski (1990) J neutrophils and T lymphocytes, and/or Immunol Methods 132, 287-295. inhibition of interferons. IL-4 mutein GeneSeq Accession DE4137333 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, Y124G R47184 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Siegel & Mostowski (1990) J neutrophils and T lymphocytes, and/or Immunol Methods 132, 287-295. inhibition of interferons. Human GeneSeq Accession WO9317698 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, Interleukin-10 R41664 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, (precursor) lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Thompson-Snipes et al (1991) J. neutrophils and T lymphocytes, and/or Exp. Med. 173, 507-510. inhibition of interferons. Human GeneSeq Accession WO9318783-A Interleukins are a group of Interleukin activity can be determined inflammatory disorders, Interleukin-10 R42642 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Thompson-Snipes et al (1991) J. neutrophils and T lymphocytes, and/or Exp. Med. 173, 507-510. inhibition of interferons. Human GeneSeq Accession EP569042 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-1 R42447 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, beta precursor. lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarello (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. Interleukin- GeneSeq Accession EP578278 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, 1alpha R45364 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq Accession JP04063595 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-3 R22814 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, variant lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Kitamura et al (1989) J Cell neutrophils and T lymphocytes, and/or Physiol. 140 323-334. inhibition of interferons. IL-1i fragments GeneSeq Accession EP541920 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R35484 and multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, R35485 lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarclio (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. IL-1 inhibitor GeneSeq Accession EPS541920 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, (IL-li) R35486 and multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, R35484 lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarclio (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. ICE 22 kD subunit. GeneSeq Accession EP533350 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R33780 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. ICE 20 kD subunit. GeneSeq Accession EP533350 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R33781 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. ICE 10 kD GeneSeq Accession EP533350 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, subunit R33782 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq Accession WO9317698 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, Interleukin-10 R41664 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, (precursor) lymphocytes, monocytes, and Matthews et al., inLymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Thompson-Snipes et al (1991) J. neutrophils and T lymphocytes, and/or Exp. Med. 173, 507-510. inhibition of interferons. Human GeneSeq Accession WO9318783 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, Interleukin-10 R42642 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Thompson-Snipes et al (1991) J. neutrophils and T lymphocytes, and/or Exp. Med. 173, 507-510. inhibition of interferons. Human GeneSeq Accession EP569042 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, Interleukin-1 R42447 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, beta precursor lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Kitamura et al (1989) J Cell neutrophils and T lymphocytes, and/or Physiol. 140 323-334. inhibition of interferons. Human GeneSeq Accession WO9403492 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-6 R49041 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Aarden et al (1987) Eur. J. neutrophils and T lymphocytes, and/or Immunol 17, 1411-16. inhibition of interferons. Mutant Interleukin 6 GeneSeq Accession WO9411402 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, S176R R54990 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Aarden et al (1987) Eur. J. neutrophils and T lymphocytes, and/or Immunol 17, 1411-16. inhibition of interferons. Interleukin 6 GeneSeq Accession JP06145063 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R55256 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Aarden et al (1987) Eur. J. neutrophils and T lymphocytes, and/or Immunol 17, 1411-16. inhibition of interferons. Interleukin 8 GeneSeq Accession JP06100595 Interleukins are a group of Interleukin activity can be determined Soluble IL-8 receptor (IL-8) receptor R53932 multifunctional cytokines synthesized by using assays known in the art: polypeptides may be lymphocytes, monocytes, and Matthews et al., in Lymphokines and useful for inhibiting macrophages. Known functions include Interferens: A Practical Approach, interleukin activities. stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Holmes et al (1991) Science 253, neutrophils and T lymphocytes, and/or 1278-80. inhibition of interferons. Human GeneSeq Accession U.S. Pat. No. 5,328,988 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-7 R59919 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Park et al (1990) J. Exp. Med. neutrophils and T lymphocytes, and/or 171, 1073-79. inhibition of interferons. IL-3 containing GeneSeq Accession WO9521254 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, fusion protein. R79342 and multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, R79344 lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Kitamura et al (1989) J Cell neutrophils and T lymphocytes, and/or Physiol. 140 323-334. inhibition of interferons. IL-3 mutant GeneSeq Accession ZA9402636 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, proteins R79254, R79255, multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, R79256, R79257, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer R79258, R79259, macrophages. Known functions include Interferens: A Practical Approach, R79260, R79261, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, R79262, R79263, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; R79264, R79265, and lymphocytes), chemotaxis of and Giri et al (1994) EMBO J. 13 R79266, R79267, neutrophils and T lymphocytes, and/or 2822-2830. R79268, R79269, inhibition of interferons. R79270, R79271, R79272, R79273, R79274, R79275, R79276, R79277, R79278, R79279, R79280, R79281, R79282, 879283, R79284, and R79285 IL-12 p40 GeneSeq Accession AU9466072 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, subunit. R63018 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. AGF GeneSeq Accession WO9429344 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R64240 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq Accession WO9519786 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interlaukin-12 40 kD R79187 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, subunit lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Hori et al (1987), Blood 70, neutrophils and T lymphocytes, and/or 1069-1078. inhibition of interferons. Human GeneSeq Accession WO9530695 Interleukins are a group of Interleukin activity can be determined Soluble IL-8 receptor interleukin-15 R90843 multifunctional cytokines synthesized by using assays known in the art: polypeptides may be receptor from lymphocytes, monocytes, and Matthews et al., in Lymphokines and useful for inhibiting clone P1 macrophages. Known functions include Interferens: A Practical Approach, interleukin activities. stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Giri et al (1994) EMBO J. 13 neutrophils and T lymphocytes, and/or 2822-2830. inhibition of interferons. Human GeneSeq Accession WO9604306 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-7 R92796 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Park et al (1990) J. Exp. Med. neutrophils and T lymphocytes, and/or 171, 1073-79. inhibition of interferons. interleukin-9 GeneSeq Accesion WO9604306 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R92797 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Yang et al (1989) Blood 74, neutrophils and T lymphocytes, and/or 1880-84. inhibition of interferons. interleukin-3 GeneSeq Accession WO9604306 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R92801 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Kitamura et al (1989) J Cell neutrophils and T lymphocytes, and/or Physiol. 140 323-334. inhibition of interferons. Human GeneSeq Accession WO9604306 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-5 R92802 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Kitamura et al (1989) J Cell neutrophils and T lymphocytes, and/or Physiol. 140 323-334. inhibition of interferons. Recombinant GeneSeq Accession DE19617202 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-16 W33373 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Lim et al (1996) J. Immunol. 156, neutrophils and T lymphocytes, and/or 2566-70. inhibition of interferons. Human IL-16 GeneSeq Accession DE19617202 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, protein W33234 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Lim et al (1996) J. Immunol. 156, neutrophils and T lymphocytes, and/or 2566-70. inhibition of interferons. Thrl 17 human GeneSeq Accession WO9708321 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin 9 W27521 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Metl 17 human GeneSeq Accession WO9708321 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin 9 W27522 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Yang et al (1989) Blood 74, neutrophils and T lymphocytes, and/or 1880-84. inhibition of interferons. Human GeneSeq Accession EP86-4585 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, intracellular IL-1 W77158 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, receptor lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer antagonist. macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarello (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. Human GeneSeq Accession EP864585 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-18 W77158 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, protein (IL-18) lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and USHIO et al (1996) J. Immunol. neutrophils and T lymphocytes, and/or 156, 4274-79. inhibition of interferons. Human GeneSeq Accession EP861663 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-18 W77077 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferens: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and USHIO et al (1996) J. Immunol. neutrophils and T lymphocytes, and/or 156, 4274-79. inhibition of interferons. Human interleukin GeneSeq Accessions EP861663 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, 18 derivatives W77083, W77084, multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, W77085, W77086, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer W77087, W77088, macrophages. Known functions include Interferons: A Practical Approach, and W77089 stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Ushio et al (1996) J. Immunol, neutrophils and T lymphocytes, and/or 156, 4274-79. inhibition of interferons. Interleukin-9 GeneSeq Accession WO9827997 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, (IL-9) mature W68158 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, protein (Thr117 lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer version). macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Yang et al (1989) Blood 74, neutrophils and T lymphocytes, and/or 1880-84. inhibition of interferons. IL-9 mature GenSeq Accession WO9827997 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, protein variant W68157 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, (Met117 version) lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Yang et al (1989) Blood 74, neutrophils and T lymphocytes, and/or 1880-84. inhibition of interferons. Human IL-9 GeneSeq Accession WO9824904 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, receptor protein W64058 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, variant #3. lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Yang et at (1989) Blood 74, neutrophils and T lymphocytes, and/or 1880-84. inhibition of interferons. Human IL-9 GenSeq Accession WO9824904 Interleukins are a group of Interleukin activity can be determined Soluble IL-9 receptor receptor protein W64060 multifunctional cytokines synthesized by using assays known in the art: polypeptides may be variant fragment lymphocytes, monocytes, and Matthews et al., in Lymphokines and useful for inhibiting macrophages. Known functions include Interferons: A Practical Approach, interleukin activities. stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Yang et al (1989) Blood 74, neutrophils and T lymphocytes, and/or 1880-84. inhibition of interferons. Human IL-9 GeneSeq Accession WO9824904 Interleukins are a group of Interleukin activity can be determined Soluble IL-9 receptor receptor protein W64061 multifunctional cytokines synthesized by using assays known in the art: polypeptides may be variant #3. lymphocytes, monocytes, and Matthews et al., in Lymphokines and useful for inhibiting macrophages. Known functions include Interferons: A Practical Approach, interleukin activities. stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Yang et at (1989) Blood 74, neutrophils and T lymphocytes, and/or 1880-84. inhibition of interferons. Human GeneSeq Accession WO9817689 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, Interleukin-12 p40 W51311 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, protein lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Hori et al (1987), Blood 70, neutrophils and T lymphocytes, and/or 1069-1078. inhibition of interferons. Human GeneSeq Accession WO9817689 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, Interleukin-12 p35 W51312 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, protein lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Hori et al (1987), Blood 70, neutrophils and T lymphocytes, and/or 1069-1078. inhibition of interferons. Human protein GeneSeq Accession DE19649233- Interleukins are a group of Interleukin activity can be determined inflammatory disorders, with IL-16 activity W63753 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Lim et al (1996) J. Immunol. 156, neutrophils and T lymphocytes, and/or 2566-70. inhibition of interferons. Human protein GeneSeq Accession DE19649233- Interleukins are a group of Interleukin activity can be determined inflammatory disorders, with IL-16 activity W59425 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Lim et al (1996) J. Immunol. 156, neutrophils and T lymphocytes, and/or 2566-70. inhibition of interferons. Human GeneSeq Accession U.S. Pat. No. 5,747,024 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-15 W53878 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Giri et al (1994) EMBO J. 13 neutrophils and T lymphocytes, and/or 2822-2830. inhibition of interferons. Human wild-type GeneSeq Accession WO9747744 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-4 (hIL- W52149 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, 4) protein lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Siegel & Mostowski (1990) J neutrophils and T lymphocytes, and/or Immunol Methods 132, 287-295. inhibition of interferons. interleukin-4 GeneSeq Accessions WO9747744 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, muteins W52150, W52151, multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, W52153, W52154, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer W52155, W52156, macrophages. Known functions include Interferons: A Practical Approach, W52157, W52158, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, W52159, W52160, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; W52161, W52162, and lymphocytes), chemotaxis of and Siegel & Mostowski (1990) J W52163, W52164, neutrophils and T lymphocytes, and/or Immunol Methods 132, 287-295. W52165, W52166, inhibition of interferons. and W52167 Human interleukin GeneSeq Accession WO9935268 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, 1 delta Y28408 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarello (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. Human GeneSeq Accession WO9935268 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-1 Y24395 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, receptor antagonist lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer beta macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL, Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarello (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. Human EDIRF II GeneSeq Accession WO9932632 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, protein sequence Y22199 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human EDIRF I GeneSeq Accession WO9932632 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, protein sequence Y22197 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cell, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL-1RD10 GeneSeq Accession WO9919480 Interleukins are a group of Interleukin activity can be determined Soluble IL-1RD10 protein sequence Y14131 multifunctional cytokines synthesized by using assays known in the art: receptor polypeptides lymphocytes, monocytes, and Matthews et al., in Lymphokines and may be useful for macrophages. Known functions include Interferons: A Practical Approach, inhibiting interleukin stimulating proliferation of immune cells Clemens et al., eds, IRL Press, activites. (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarello (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. Human IL-1RD9 GeneSeq Accession WO9919480 Interleukins are a group of Interleukin activity can be determined Soluble IL-1RD10 Y14122 multifunctional cytokines synthesized by using assays known in the art: receptor polypeptides lymphocytes, monocytes, and Matthews et al., in Lymphokines and may be useful for macrophages. Known functions include Interferons: A Practical Approach, inhibiting interleukin stimulating proliferation of immune cells Clemens et al., eds, IRL Press, activites. (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarello (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. Human DNAX GeneSeq Accession WO9919491 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, interleukin-40 Y09196 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. (DIL-40) GeneSeq Accession WO9919491 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, alternative Y09197 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, sequence lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-11 GeneSeq Accession WO9405318 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R50176 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Lu et al (1994) J immunol. neutrophils and T lymphocytes, and/or Methods 173, 19. inhibition of interferons. Human GeneSeq Accession EP566410 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, adipogenesis R43260 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, inhibitory factor lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-11 GeneSeq Accession JP08127539 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, W02202 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Lu et al (1994) J immunol. neutrophils and T lymphocytes, and/or Methods 173, 19. inhibition of interferons. IL-14 GeneSeq Accession WO9416074 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R55800 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Ambrus et al (1993) PNAS 90, neutrophils and T lymphocytes, and/or 63330-34. inhibition of interferons. IL-17 receptor GeneSeq Accession U.S. Pat. No. 6,072,033 Interleukins are a group of Interleukin activity can be determined Soluble IL-17 receptor B03807 multifunctional cytokines synthesized by using assays known in the art: polypeptides may be lymphocytes, monocytes, and Matthews et al., in Lymphokines and useful for inhibiting macrophages. Known functions include Interferons: A Practical Approach, interleukin activities. stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Yao et al (1995) J. Immunol. 155, neutrophils and T lymphocytes, and/or 5483-86. inhibition of interferons. IL-17 GeneSeq Accession WO9518826 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, R76573 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Yao et al (1995) J. Immunol. 155, neutrophils and T lymphocytes, and/or 5483-86. inhibition of interferons. CTLA-8 GeneSeq Accession WO9704097 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, W13651 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225. and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-19 GeneSeq Accession WO9808870 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, W37935 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Gallagher et al (2000) Genes neutrophils and T lymphocytes, and/or Immun. 1, 442-50. inhibition of interferons. IL-21 (TIF) GeneSeq Accession WO0024758 Interleukins are a group of Interleukin activity can be determined inflammatory disorders, Y92879 multifunctional cytokines synthesized by using assays known in the art: immunologic disorders, lymphocytes, monocytes, and Matthews et al., in Lymphokines and cancer macrophages. Known functions include Interferons: A Practical Approach, stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Parrish-Novak et al (2000) neutrophils and T lymphocytes, and/or Nature 408, 57-63. inhibition of interferons. IL-8 receptor GeneSeq Accession WO9306229 Interleukins are a group of Interleukin activity can be determined Soluble IL-8 receptor R33420 multifunctional cytokines synthesized by using assays known in the art: polypeptides may be lymphocytes, monocytes, and Matthews et al., in Lymphokines and useful for inhibiting macrophages. Known functions include Interferons: A Practical Approach, interleukin activities. stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Holmes et al (1991) Science 253, neutrophils and T lymphocytes, and/or 1278-80. inhibition of interferons. Human type II GeneSeq Accession U.S. Pat. No. 5,464,937 Interleukins are a group of Interleukin activity can be determined Soluble type II interleukin-1 R85480 multifunctional cytokines synthesized by using assays known in the art: interleukin-1 receptor receptor lymphocytes, monocytes, and Matthews et al., in Lymphokines and polypeptides may be macrophages. Known functions include Interferons: A Practical Approach, useful for inhibiting stimulating proliferation of immune cells Clemens et al., eds. IRL Press, interleukin activities. (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Orencole & Dinarello (1989) neutrophils and T lymphocytes, and/or Cytokine 1, 14-20. inhibition of interferons. Human GeneSeq Accession EP638644 Interleukins are a group of Interleukin activity can be determined Soluble IL-12 receptor interleukin-12 R69632 multifunctional cytokines synthesized by using assays known in the art: polypeptides may be receptor lymphocytes, monocytes, and Matthews et al., in Lymphokines and useful for inhibiting macrophages. Known functions include Interferons: A Practical Approach, interleukin activities. stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Hori et al (1987), Blood 70, neutrophils and T lymphocytes, and/or 1069-1078. inhibition of interferons. Interleukin 8 GeneSeq Accession U.S. Pat. No. 5,440,021 Interleukins are a group of Interleukin activity can be determined Soluble IL-8 receptor B receptor B R80758 multifunctional cytokines synthesized by using assays known in the art: polypeptides may be lymphocytes, monocytes, and Matthews et al., in Lymphokines and useful for inhibiting macrophages. Known functions include Interferons: A Practical Approach, interleukin activities. stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Holmes et al (1991) Science 253, neutrophils and T lymphocytes, and/or 1278-80. inhibition of interferons. Human IL-8 GeneSeq Accession JP08103276 Interleukins are a group of Interleukin activity can be determined Soluble IL-8 receptor A receptor protein B09989 multifunctional cytokines synthesized by using assays known in the art: polypeptides may be hIL8RA lymphocytes, monocytes, and Matthews et al., in Lymphokines and useful for inhibiting macrophages. Known functions include Interferons: A Practical Approach, interleukin activities. stimulating proliferation of immune cells Clemens et al., eds, IRL Press, (e.g., T helper cells, B cells, eosinophils, Washington, D.C. 1987, pp. 221-225; and lymphocytes), chemotaxis of and Holmes et al (1991) Science 253, neutrophils and T lymphocytes, and/or 1278-80. inhibition of interferons. Human IL-8 GeneSeq Accession JP08103276 Interleukins are a group of Interleukin activity can be Soluble IL-8 receptor receptor protein B09990 multifunctional cytokines synthesized determined using asays known in the polypeptides may be hIL8R by lymphocytes, monocytes, and art: Matthews et al., in Lymphokines useful for inhibiting macrophages. Known functions include and Interferons: A Practical interleukin activities. stimulating proliferation of immune Approach, Clemens et al., eds, IRL cells (e.g., T helper cells, B cells, Press, Washington, D.C. 1987, pp. eosinophils, and lymphocytes), 221-225; and Holmes et al (1991) chemotaxis of neutrophils and T Science 253, 1278-80. lymphocytes, and/or inhibition of interferons. Interleukin-2 GeneSeq Accession WO9621732 Interleukins are a group of Interleukin activity can be Soluble IL-2 receptor receptor associated R97569 multifunctional cytokines synthesized determined using assays known in polypeptides may be protein p43 by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Gillis et al chemotaxis of neutrophils and T (1978) J. Immunol. 120, 2027. lymphocytes, and/or inhibition of interferons. Human GeneSeq Accession WO9629408 Interleukins are a group of Interleukin activity can be Soluble IL-17 receptor interleukin-17 W04185 multifunctional cytokines synthesized determined using assays known in polypeptides may be receptor by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Yao et al chemotaxis of neutrophils and T (1995) J. Immunol. 155, 5483-86. lymphocytes, and/or inhibition of interferons. Human GeneSeq Accession WO9619574 Interleukins are a group of Interleukin activity can be Soluble IL-11 receptor interleukin-11 R99090 multifunctional cytokines synthesized determined using assays known in polypeptides may be receptor by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Lu et al chemotaxis of neutrophils and T (1994) J immunol. Methods 173, 19. lymphocytes, and/or inhibition of interferons. Human GeneSeq Accession WO9623067 Interleukins are a group of Interleukin activity can be Inflammatory disorders, interleukin-1 W01911 multifunctional cytokines synthesized determined using assays known in immunologic disorders, receptor accessory by lymphocytes, monocytes, and the art: Matthews et al., in cancer protein macrophages. Known functions include Lymphokines and Interferons: A stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Orencole & chemotaxis of neutrophils and T Dinarello (1989) Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. AGF Protein GeneSeq Accession U.S. Pat. No. 5,488,032 Interleukins are a group of Interleukin activity can be Inflammatory disorders, R92749 multifunctional cytokines synthesized determined using assays known in immunologic disorders, by lymphocytes, monocytes, and the art: Matthews et al., in cancer macrophages. Known functions include Lymphokines and Interferons: A stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq Accession W09607739 Interleukins are a group of Interleukin activity can be Soluble IL-type-3 interleukin-1 type- R91064 multifunctional cytokines synthesized determined using assays known in receptor polypeptides 3 receptor by lymphocytes, monocytes, and the art: Matthews et al., in may be useful for macrophages. Known functions include Lymphokines and Interferons: A inhibiting interleukin stimulating proliferation of immune Practical Approach, Clemens et al., activities cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Orencole & chemotaxis of neutrophils and T Dinarello (1989) Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. Human GeneSeq Accession WO9720926 Interleukins are a group of Interleukin activity can be Soluble IL-13 beta interleukin-13 beta W24972 multifunctional cytokines synthesized determined using assays known in receptor polypeptides receptor by lymphocytes, monocytes, and the art: Matthews et al., in may be useful for macrophages. Known functions include Lymphokines and Interferons: A inhibiting interleukin stimulating proliferation of immune Practical Approach, Clemens et al., activities. cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Boutelier et chemotaxis of neutrophils and T al (1995) J. Immunol. Methods lymphocytes, and/or inhibition of 181, 29. interferons. Human GeneSeq Accession WO9720926 Interleukins are a group of Interleukin activity can be Soluble IL-13 alpha interleukin-13 W24973 multifunctional cytokines synthesized determined using assays known in receptor polypeptides alpha receptor by lymphocytes, monocytes, and the art: Matthews et al., in may be useful for macrophages. Known functions include Lymphokines and Interferons: A inhibiting interleukin stimulating proliferation of immune Practical Approach, Clemens et al., activities. cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Boutelier et chemotaxis of neutrophils and T al (1995) J. Immunol. Methods lymphocytes, and/or inhibition of 181, 29. interferons. Human GeneSeq Accession U.S. Pat. No. 5,599,905 Interleukins are a group of Interleukin activity can be Soluble IL-4 receptor interleukin-4 W13499 multifunctional cytokines synthesized determined using assays known in polypeptides may be receptor by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Siegel & chemotaxis of neutrophils and T Mostowski (1990) J Immunol lymphocytes, and/or inhibition of Methods 132, 287-295. interferons. Human GeneSeq Accession EP759466 Interleukins are a group of Interleukin activity can be Soluble IL-12 beta-2 interleukin-12 W12771 multifunctional cytokines synthesized determined using assays known in receptor polypeptides beta-2 receptor by lymphocytes, monocytes, and the art: Matthews et al., in may be useful for macrophages. Known functions include Lymphokines and Interferons: A inhibiting interleukin stimulating proliferation of immune Practical Approach, Clemens et al., activities. cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Hori et al chemotaxis of neutrophils and T (1987), Blood 70, 1069-1078. lymphocytes, and/or inhibition of interferons. Human GeneSeq Accession EP759466 Interleukins are a group of Interleukin activity can be Soluble IL-12 beta-1 interleukin-12 W12772 multifunctional cytokines synthesized determined using assays known in receptor polypeptides beta-1 receptor. by lymphocytes, monocytes, and the art: Matthews et al., in may be useful for macrophages. Known functions include Lymphokines and Interferons: A inhibiting interleukin stimulating proliferation of immune Practical Approach, Clemens et al., activities. cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Hori et at chemotaxis of neutrophils and T (1987), Blood 70, 1069-1078. lymphocytes, and/or inhibition of interferons. Human IL-9 GeneSeq Accessions WO9824904 Interleukins are a group of Interleukin activity can be Soluble IL-9 receptor receptor protein W64055, W64056, multifunctional cytokines synthesized determined using assays known in polypeptides may be and W64057 by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Yang et al chemotaxis of neutrophils and T (1989), Blood 74, 1880-84.. lymphocytes, and/or inhibition of interferons. IL-10 receptor GeneSeq Accession U.S. Pat. No. 5,716,804 Interleukins are a group of Interleukin activity can be Soluble IL-10 receptor W41804 multifunctional cytokines synthesized determined using assays known in polypeptides may be by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Thompson- chemotaxis of neutrophils and T Snipes et al (1991) J. Exp. Med. 173, lymphocytes, and/or inhibition of 507-510. interferons. Human IL-6 GeneSeq Accession JP11196867 Interleukins are a group of Interleukin activity can be Soluble IL-6 receptor receptor Y30938 multifunctional cytokines synthesized determined using assays known in polypeptides may be by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Aarden et al chemotaxis of neutrophils and T (1987) Eur. J. Immunol 17, 1411-16. lymphocytes, and/or inhibition of interferons. Il-17 receptor GeneSeq Accession U.S. Pat. No. 6,096,305 Interleukins are a group of Interleukin activity can be Soluble IL-17 receptor Y97181 multifunctional cytokines synthesized determined using assays known in polypeptides may be by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Yao et al chemotaxis of neutrophils and T (1995) J. Immunol. 155, 5483-86. lymphocytes, and/or inhibition of interferons. Il-17 receptor GeneSeq Accession U.S. Pat. No. 6,100,235 Interleukins are a group of Interleukin activity can be Soluble IL-17 receptor Y97131 multifunctional cytokines synthesized determined using assays known in polypeptides may be by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Yao et al chemotaxis of neutrophils and T (1995) J. Immunol. 155, 5483-86. lymphocytes, and/or inhibition of interferons. Human GeneSeq Accession EP509826 Interleukins are a group of Interleukin activity can be Soluble IL-3 receptor interleukin-3 R25300 multifunctional cytokines synthesized determined using assays known in polypeptides may be receptor by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL, Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Kitamura et chemotaxis of neutrophils and T al (1989) J Cell Physiol. 140 323-334. lymphocytes, and/or inhibition of interferons. Human GM-CSF GeneSeq Accession WO9102063 Interleukins are a group of Interleukin activity can be Soluble GM-CSF receptor R10919 multifunctional cytokines synthesized determined using assays known in receptor polypeptides by lymphocytes, monocytes, and the art: Matthews et al., in may be useful for macrophages. Known functions include Lymphokines and Interferons: A inhibiting interleukin stimulating proliferation of immune Practical Approach, Clemens et al., activities. cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL-5 GeneSeq Accession EP492214 Interleukins are a group of Interleukin activity can be Soluble IL-5 receptor receptor alpha R25064 multifunctional cytokines synthesized determined using assays known in alpha polypeptides may chain by lymphocytes, monocytes, and the art: Matthews et al., in be useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Kitamura et chemotaxis of neutrophils and T al (1989) J Cell Physiol. 140, 323-334. lymphocytes, and/or inhibition of interferons. Il-5 receptor GeneSeq Accession WO9847923 Interleukins are a group of Interleukin activity can be Soluble IL-5 receptor W82842 multifunctional cytokines synthesized determined using assays known in polypeptides may be by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Kitamura et chemotaxis of neutrophils and T al (1989) J Cell Physiol. 140, 323-334. lymphocytes, and/or inhibition of interferons. Il-6 receptor GeneSeq Accession JP05091892 Interleukins are a group of Interleukin activity can be Soluble IL-6 receptor R37215 multifunctional cytokines synthesized determined using assays known in polypeptides may be by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Aarden et al chemotaxis of neutrophils and T (1987) Eur. J. Immunol 17, 1411-16. lymphocytes, and/or inhibition of interferons. Human B cell GeneSeq Accession AU8928720 Interleukins are a group of Interleukin activity can be Soluble B cell stimulating factor- P90525 multifunctional cytokines synthesized determined using assays known in stimulating factor-2 2 receptor by lymphocytes, monocytes, and the art: Matthews et al., in receptor polypeptides macrophages. Known functions include Lymphokines and Interferons: A may be useful for stimulating proliferation of immune Practical Approach, Clemens et al., inhibiting interleukin cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. activities. eosinophils, and lymphocytes), 1987, pp. 221-225. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-7 receptor clone GeneSeq Accession EP403114 Interleukins are a group of Interleukin activity can be Soluble IL-7 receptor R08330 multifunctional cytokines synthesized determined using assays known in polypeptides may be by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Park et al chemotaxis of neutrophils and T (1990) J. Exp. Med. 171, 1073-79. lymphocytes, and/or inhibition of interferons. EPO receptor; GeneSeq Accession WO9008822 EPO Receptor is involved in the EPO Receptor activity can be Inflammatory disorders, EPOR R06512 proliferation and differentiation of determined using assays known in immunologic disorders, erythroblasts. the art, such as, J Biol Chem 2001 cancer, erythroblast Mar. 23; 276(12: 8995-9002; JAK2 proliferation and protein tyrosine kinase activity: differentiation Blood 1994 Sep. 1; 84(5): 1501-7 and Mol Cell Biol. 1994 October; 14(10: 6506-14. IL-15 receptor GeneSeq Accession WO9530695 Interleukins are a group of Interleukin activity can be Soluble IL-15 receptor R90843 multifunctional cytokines synthesized determined using assays known in polypeptides may be by lymphocytes, monocytes, and the art: Matthews et al., in useful for inhibiting macrophages. Known functions include Lymphokines and Interferons: A interleukin activities. stimulating proliferation of immune Practical Approach, Clemens et al., cells (e.g., T helper cells, B cells, eds, IRL Press, Washington, D.C. eosinophils, and lymphocytes), 1987, pp. 221-225; and Giri et al chemotaxis of neutrophils and T (1994) EMBO J. 13 2822-2830. lymphocytes, and/or inhibition of interferons. CD137; 4-1BB GeneSeq Accession WO9507984 Activities associated with apoptosis, Apoptosis activity, NF-kB Soluble 4-1BB receptor Receptor Protein R70977 NF-kB activation, and co-stimulation of activation, and B and T cell co- polypeptides may be immune cells such as T and B cells. stimulation can be determined using useful for inhibiting assays known in the art: Moore et apoptosis, NF-kB al., 1999, Science, 285(5425): 260-3; activation, and/or co- Song H Y et al., 1997 Proc Natl Acad stimulation of immune Sci USA 94(18): 9792-6; Epsevik cells such as B and T and Nissen-Meyer, 1986, J. cells. Immunol. Methods. BCMA GeneSeq Accession WO0068378 Activities associated with apoptosis, Apoptosis activity, NF-kB Soluble BCMA receptor Y71979 NF-kB activation, and co-stimulation of activation, and B and T cell co- polypeptides may be immune cells such as T and B cells. stimulation can be determined using useful for inhibiting assays known in the art: Moore et apoptosis, NF-kB al., 1999, Science, 285(5425): 260-3; activation, and/or co- Song H Y et al., 1997 Proc Natl Acad stimulation of immune Sci USA 94(18): 9792-6; Epsevik cells such as B and T and Nissen-Meyer, 1986, J. cells. Immunol. Methods. CD27 GeneSeq Accession WO9201049 Activities associated with apoptosis, Apoptosis activity, NF-kB Soluble CD27 R20814 NF-kB activation, and co-stimulation of activation, and B and T cell co- polypeptides may be immune cells such as T and B cells. stimulation can be determined using useful for inhibiting assays known in the art: Moore et apoptosis, NF-kB al., 1999, Science, 285(5425): 260-3; activation, and/or co- Song H Y et al., 1997 Proc Natl Acad stimulation of immune Sci USA 94(18): 9792-6; Epsevik cells such as B and T and Nissen-Meyer, 1986, J. cells. Immunol. Methods. CD30 GeneSeq Accession DE4200043 Activities associated with apoptosis, Apoptosis activity, NF-kB Soluble CD30 R35478 NF-kB activation, and co-stimulation of activation, and B and T cell co- polypeptides may be immune cells such as T and B cells. stimulation can be determined using useful for inhibiting assays known in the art: Moore et apoptosis, NF-kB al., 1999, Science, 285(5425): 260-3; activation, and/or co- Song H Y et al., 1997 Proc Natl Acad stimulation of immune Sci USA 94(18): 9792-6; Epsevik cells such as B and T and Nissen-Meyer, 1986, J. cells. Immunol. Methods. CD40 GeneSeq Accession WO9945944 Activities associated with apoptosis, Apoptosis activity, NF-kB Soluble CD40 Y33499 NF-kB activation, and co-stimulation of activation, and B and T cell polypeptides may be immune cells such as T and B cells. co-stimulation can be determined useful for inhibiting using assays known in the art: apoptosis, NF-kB Moore et al., 1999, Science activation, and/or co- 285(5425): 260-3; Song H Y et al., stimulation of immune 1997 Proc Natl Acad Sci USA cells such as B and T 94(18): 9792-6; Epsevik and cells. Nissen-Meyer, 1986, J. Immunol. Methods. EDAR Genbank Accession Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Immune Disorders, AAD50077 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can Lymphomas, X-linked immune cells such as T and B cells. be determined using assays known in hypohidrotic ectodermal the art: Moore et al., 1999, Science, dysplasia 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. OX40; ACT-4 GeneSeq Accession WO9512673 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Immune Disorders, R74737 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can Lymphomas, T cell immune cells such as T and B cells. be determined using assays known in disorders the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. TACI GeneSeq Accession WO9839361 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble TACI receptor W75783 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can polypeptides may be immune cells such as T and B cells. be determined using assays known in useful for inhibiting the art: Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song H Y et al., activation, and/or co- 1997 Proc Natl Acad Sci USA stimulation of immune 94(18): 9792-6; Epsevik and Nissen- cells such as B and T Meyer, 1986, J. Immunol. Methods. cells. TNF-R GeneSeq Accession AU9058976 Activities associates with apoptosis, Apoptosis activity, NF-kB Soluble TNF-R receptor R10986 NF-kB activation, and co-stimulation of activation, and B and T cell co- polypeptides may be immune cells such as T and B cells. stimulation can be determined using useful for inhibiting assays known in the art: Moore et al., apoptosis, NF-kB 1999, Science, 285(5425): 260-3; activation, and/or co- Song H Y et al., 1997 Proc Natl Acad stimulation of immune Sci USA 94(18): 9792-6; Epsevik cells such as B and T and Nissen-Meyer, 1986, J. Immunol. cells. Methods. TNF-RII; TNF GeneSeq Accession EP418014 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble TNFR-II p75 receptor; R11141 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can receptor polypeptides Death Receptor immune cells such as T and B cells. be determined using assays known in may be useful for the art: Moore et al., 1999, Science, inhibiting apoptosis, 285(5425): 260-3; Song H Y et al., NF-kB activation, 1997 Proc Natl Acad Sci USA and/or co-stimulation of 94(18)9792-6; Epsevik and Nissen- immune cells such as B Meyer, 1986, J. Immunol. Methods. and T cells. hAPO-4; TROY GeneSeq Accession WO9911791 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Immune Disorders, W93581 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can Cancers immune cells such as T and B cells. be determined using assays known in the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. TNF-alpha GeneSeq Accession EP205038 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, precursor P60074 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. Human TNF- GeneSeq Accession EP619372 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, alpha R62463 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells be determined using assays known in cancer the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. Human TNF- GeneSeq Accession EP563714 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, alpha R42679 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. Human TNF- GeneSeq Accession WO0064479 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, beta (LT-alpha) B37799 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. LT-alpha GeneSeq Accession EP250000 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, P70107 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. LT-beta GeneSeq Accession WO9413808 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, R56869 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18)9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. OPGL GeneSeq Accession WO9846751 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, W83195 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer, loss of bone the art: Moore et al., 1999, Science, mass 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18)9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. FasL GeneSeq Accession WO9903999 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, W98071 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore, et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18)9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. FasL GeneSeq Accession WO9903998 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, W95041 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can imunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. CD27L GeneSeq Accession WO9405691 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, R50121 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. CD30 ligand GeneSeq Accession WO9324135 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, R45007 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. CD40L GeneSeq Accession WO9529935 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, R85486 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore, et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. 4-1BB ligand GeneSeq Accession U.S. Pat. No. 5,674,704 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, W26657 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. FAS Ligand GeneSeq Accession WO0058465 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble DcR3 Inhibitory B19335 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can polypeptides may be Protein (DcR3) immune cells such as T and B cells. be determined using assays known in useful for inhibiting the art: Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song H Y et al., activation, and/or co- 1997 Proc Natl Acad Sci USA stimulation of immune 94(18): 9792-6; Epsevik and Nissen- cells such as B and T Meyer, 1986, J. Immunol. Methods cells. OX40L GeneSeq Accession WO9521915 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory disorders, R79903 NF-kB activation, and co-stimulation of and B and T cell co-stimulation can immunologic disorders, immune cells such as T and B cells. be determined using assays known in cancer the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen- Meyer, 1986, J. Immunol. Methods. Protease GeneSeq Accessions WO9106561 Peptides that inhibit the function/binding HIV protease activities are known in HIV, inflammatory inhibitor R12435, R12436, of HIV the art: HIV protease assays: disorders, immunologic peptides R12437, R12438, EP0387231. One can modify the disorders, cancer, viral R12439, R12440, assay to look for inhibition using any infections and R1244 of the disclosed protease inhibitor polypeptides. Retroviral protease GeneSeq Accessions EP387231 Peptides that inhibit the function/binding HIV protease activities are known in HIV, inflammatory inhibitors R06660, R06661, of HIV the art: HIV protease assays: disorders, immunologic R06662, R06663, EP0387231. One can modify the disorders, cancer, viral R06664, R06665, assay to look for inhibition using any infections R06666, R06667, of the disclosed protease inhibitor R06668, R06669, polypeptides. R06670, R06671, R06672, R06673, R06674, R06675, and R06676 HIV protease GeneSeq Accessions WO9301828 Peptides that inhibit the function/binding of HIV protease activities are known in the HIV, inflammatory inhibiting R59293, R59294, HIV art: HIV protease assays: EP0387231. disorders, immunologic peptides R59295, R59296, One can modify, the assay to look for disorders, cancer, viral R59297, R59298, inhibition using any of the disclosed infections R59299, R592300, protease inhibitor polypeptides. R59301, R59302, R59301, R59302, R59303, R59304, R59305, R59306, R59307, R59308, R59309, R59310, R59311, R59312, R59313, R59314, R59315, R59316, R59317 R59318, R59319, R59320, R59321, R59322, R59323, R59324, R59325, R59326, R59327, R59328, R59329, R59330, R59331, R59332, R59333, R59334, R59335, R59336, R59337, R59338, R59339, R59340, R59341, R59342, R59343, R59344, R59345, R59346, R59347, R59348, R59349, and R59350 HIV-1 protease GeneSeq Accessions DE4412174 Peptides that inhibit the function/binding of HIV protease activities are known in the HIV, inflammatory hinibitors R86326, R86327, HIV art: HIV protease assays: EP0387231. disorders, immunologic R86328, R86329, One can modify the assay to look for disorders, cancer, viral R86330, R86331, inhibition using any of the disclosed infections R86332, R86333, protease inhibitor polypeptides. R86334, R86335, R86336, R86337, R86338, R86339, R86340, R86341, R86342, R86343, R86344, R86345, R86346, R86347, R86348, R86349, R86350, R86351, R86352, R86353, R86354, R86355, R86356, R86357, R86358, R86359, R86360, R86361, R86362, R86363, R86364, R86365, R86366, R86367, R86368, R86369, R86370, and R86371 HIV Inhibitor GeneSeq Accession WO9959615 Peptides that inhibit the function/binding HIV protease activities are known in HIV, inflammatory Peptide Y89687 of HIV the art: HIV protease assays: disorders, immunologic EP0387231. One can modify the disorders, cancer, viral assay to look for inhibition using any infections of the disclosed protease inhibitor polypeptides. HIV Inhibitor GenSeq Accession WO9948513 Peptides that inhibit the function/binding HIV Protease activities are known in HIV, inflammatory Peptide Y31955 of HIV the art; HIV protease assays: disorders, immunologic EP0387231. One can modify the disorders, cancer, viral assay to look for inhibition using any infections. of the disclosed protease inhibitor polypeptides. HIV Inhibitor www.sciencexpress.org; Peptides that inhibit the function/binding HIV protease activities are known in HIV, inflammatory Peptide Published online of HIV the art: HIV protease assays: disorders, immunologic 12 Jan. 2001; EP0387231: One can modify the disorders, cancer, viral 10.1126/science.1057453 assay to look for inhibition using any infections of the disclosed protease inhibitor polypeptides. Human monocyte GeneSeq Accession WO9509232 Chemokines are a family of small, Chemokine activities can be Immune disorders, chemoattractant R73915 secreted proteins involved in biological determined using assays known in particularly useful for factor hMCP-3 processes ranging from hematopoiesis, the art: Methods in Molecular treating bacterial and/or angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine viral menigitis Members of this family are involved in a Protocols, Edited by: A. E. I. Proudfoot, similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to −17 receptors thus far identified. Human monocyte GeneSeq Accession WO9509232 Chemokines are a family of related Chemokine activities can be Immune disorders, chemoattractant R73914 small, secreted proteins involved in determined using assays known in particularly useful for factor hMCP-1 biological processes ranging from the art: Methods in Molecular treating bacterial and/or hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine viral menigitis leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to −17 receptors thus far identified. Human gro-beta GeneSeq Accessions WO9429341 Chemokines are a family of small, Chemokine activities can be immune disorders, chemokine R66699 and secreted proteins involved in biological determined using assays known in inflammatory disorders, W17671 processes ranging from hematopoiesis, the art: Methods in Molecular blood-related disorders, angiogenesis, and leukocyte trafficking. Biology, 2000, vol. 138: Chemokine stem cell Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, transplantation, cancer similarly diverse range of pathologies T. N. C. Wells, and C. A. Power. including inflammation, allergy, tissue  ©Humana Press Inc., rejection, viral infection, and tumor Totowa, NJ. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to −17 receptors thus far identified. Human gro- GeneSeq Accessions WO9429341 Chemokines are a family of related Chemokine activities can be Immune disorders, gamma chemokine R66700 and small, secreted proteins involved in determined using assays known in inflammatory disorders, W17672 biological processes ranging from the art: Methods in Molecular blood-related disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine stem cell leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, transplantation, cancer family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to −17 receptors thus far identified Human gro-alpha GeneSeq Accessions WO9429341 Chemokines are a family of related Chemokine activities can be Immune disorders, chemokine R66698 and small, secreted proteins involved in determined using assays known in inflammatory disorders, W18024 biological processes ranging from the art: Methods in Molecular blood-related disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine stem cell leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, transplantation, cancer family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to −17 receptors thus far identified Human eosinophil- GeneSeq Accession WO9632481 Chemokines are a family of related Chemokine activities can be Immune disorders, expressed W05186 small, secreted proteins involved in determined using assays known in particularly treatment of chemokine (EEC) biological processes ranging from the art: Methods in Molecular eosinophilia, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine inflammation, allergies, leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, asthma, leukaemia and family are involved in a similarly T. N. C. Wells, and C. A. Power. lymphoma diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to −17 receptors thus far identified Chemokine-like GeneSeq Accessions WO9613587 Chemokines are a family of related Chemokine activities can be Cancer and blood- protein PF4-414 R92318 and small, secreted proteins involved in determined using assays known in related disorders, Full-Length and R99809 biological processes ranging from the art: Methods in Molecular particularly Mature hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine myelosuppression leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to −17 receptors thus far identified Chemokine-like GeneSeq Accession WO9613587 Chemokines are a family of related Chemokine activities can be Cancer and blood- protein IL-8M3 R99812 small, secreted proteins involved in determined using assays known in related disorders, biological processes ranging from the art: Methods in Molecular particularly hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine myelosuppression leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ; and Holmes et al (1991) viral infection, and tumor biology. The Science 253, 1278-80. chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to −17 receptors thus far identified Human GeneSeq Accession WO9613587 Chemokines are a family of related Chemokine activities can be Cancer and blood- interleukin-8 R99814 small, secreted proteins involved in determined using assays known in related disorders, (IL-8) biological processes ranging from the art: Methods in Molecular particularly hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine myelosuppression leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ; and Holmes et al (1991) viral infection, and tumor biology. The Science 253, 1278-80. chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to −17 receptors thus far identified Chemokine-like GeneSeq Accessions WO9613587 Chemokines are a family of related Chemokine activities can be Cancer and blood- protein IL-8M1 R99815 and small, secreted proteins involved in determined using assays known in related disorders, Full-Length and R99803 biological processes ranging from the art: Methods in Molecular particularly Mature hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine myelosuppression leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ; and Holmes et al (1991) viral infection, and tumor biology. The Science 253, 1278-80. chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to −17 receptors thus far identified Chemokine-like GeneSeq Accessions WO9613587 Chemokines are a family of related Chemokine activities can be Cancer and blood- protein IL-8M8 R99816 and small, secreted proteins involved in determined using assasys known in related disorders, Full-Length and R99805 biological processes ranging from the art: Methods in Molecular particularly Mature hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine myelosuppression. leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ; and Holmes et al (1991) viral infection, and tumor biology. The Science 253, 1278-80. chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq Accessions WO9613587 Chemokines are a family of related Chemokine activities can be Cancer and blood- protein IL-8M8 R99817 and small, secreted proteins involved in determined using assasys known in related disorders, Full-Length and R99806 biological processes ranging from the art: Methods in Molecular particularly Mature hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine myelosuppression. leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ; and Holmes et al (1991) viral infection, and tumor biology. The Science 253, 1278-80. chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq Accessions WO9613587 Chemokines are a family of related Chemokine activities can be Cancer and blood- protein IL-8M8 R99818 and small, secreted proteins involved in determined using assasys known in related disorders, Full-Length and R99804 biological processes ranging from the art: Methods in Molecular particularly Mature hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine myelosuppression. leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ; and Holmes et al (1991) viral infection, and tumor biology. The Science 253, 1278-80. chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq Accessions WO9613587 Chemokines are a family of related Chemokine activities can be Cancer and blood- protein IL-8M8 R99819 and small, secreted proteins involved in determined using assasys known in related disorders, Full-Length and R99807 biological processes ranging from the art: Methods in Molecular particularly Mature hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine myelosuppression. leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq Accessions WO9613587 Chemokines are a family of related Chemokine activities can be Cancer and blood- protein IL-8M8 R99822 and small, secreted proteins involved in determined using assasys known in related disorders, Full-Length and R9807 biological processes ranging from the art: Methods in Molecular particularly Mature hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine myelosuppression. leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human foetal GeneSeq Accession WO9622374 Chemokines are a family of related Chemokine activities can be Immune disorders spleen expressed R98499 small, secreted proteins involved in determined using assasys known in chemokine, FSEC biological processes ranging from the art: Methods in Molecular hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Liver expressed GeneSeq Accession WO9616979 Chemokines are a family of related Chemokine activities can be Inflammation of the chemokine- R95689 small, secreted proteins involved in determined using assasys known in liver 1(LVEC-1) biological processes ranging from the art: Methods in Molecular hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Liver expressed GeneSeq Accession WO9616979 Chemokines are a family of related Chemokine activities can be Inflammation of the chemokine- R95690 small, secreted proteins involved in determined using assasys known in liver 2(LVEC-2) biological processes ranging from the art: Methods in Molecular hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Pituitary expressed GeneSeq Accession WO9616979 Chemokines are a family of related Chemokine activities can be Inflammation, chemokine R95691 small, secreted proteins involved in determined using assasys known in particularly of the liver (PGEC) biological processes ranging from the art: Methods in Molecular hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines liave been described, which bind to ~17 receptors thus far identified. Adenoid-expressed GeneSeq Accession WO9617868 Chemokines are a family of related Chemokine activities can be Inflammation, chemokine R97664 small, secreted proteins involved in determined using assasys known in angiogenesis, (ADEC) biological processes ranging from the art: Methods in Molecular tumorigenesis, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine musculoskeletal leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; disorders family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq Accession Chemokines are a family of related Chemokine activities can be Immune disorders, cell chemokineCC-2 W38170 small, secreted proteins involved in determined using assays known in migration, proliferation, biological processes ranging from the art: Methods in Molecular and differentiation, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138; Chemokine disorders leukocyte trafficking. Members of this protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc. inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq Accession WO9741230 Chemokines are a family of related Chemokine activities can be Immune disorders, cell chemokine W38171 small, secreted proteins involved in determined using assays known in the migration, proliferation, HCC-1 biological processes ranging from art: Methods in molecular Biology and differentiation hematopiesis, anglogenesis and 2000, vol. 138: Chemokine disorders leukocyte trafficking. Members of this Protocols. Edited by A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq Accession WO9741230 Chemokines are a family of related Chemokine activities can be Immune disorders, cell chemokine CC-3 W38172 small, secreted proteins involved in determined using assays known in the migration, proliferation biological processes ranging from art: Methods in molecular Biology, and differentiation hemotopoiesis, anglogenesis, and 2000, vol. 138: Chemokine disorders leukocyte trafficking. Members of this Protocols, Edited by A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Novel GeneSeq Accession WO9739126 Chemokines are a family of related Chemokine activities can be Immune disorders, betachemokine W27271 small, secreted proteins involved in determined using assays known in the vascular disorders, designated PTEC biological processes ranging from art: Methods in molecular Biology, cancer hemotopoiesis, anglogenesis, and 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols, Edited by A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CX3C GeneSeq Accession WO9727299 Chemokines are a family of related Chemokine activities can be Immune disorders, 111 amino acid W23344 small, secreted proteins involved in determined using assays known in the inflammatory diseases, chemokine biological processes ranging from art: Methods in molecular Biology, abnormal proliferation, hemotopoiesis, anglogenesis, and 2000, vol. 138: Chemokine regeneration, leukocyte trafficking. Members of this Protocols, Edited by A. E. I. Proudfoot, degeneration, and family are involved in a similarly T. N. C. Wells, and C. A. Power atrophy diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CCF18 GeneSeq Accession WO9721812 Chemokines are a family of related Chemokine activities can be Abnormal physiology chemokine W25942 small, secreted proteins involved in determined using assays known in the and development biological processes ranging from art: Methods in molecular Biology, disorders, can also be hemotopoiesis, anglogenesis, and 2000, vol. 138: Chemokine used as an anti-viral leukocyte trafficking. Members of this Protocols, Edited by A. E. I. Proudfoot, agent family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human beta- GeneSeq Accession WO9725427 Chemokines are a family of related Chemokine activities can be Chemotaxis, chemokine W26655 small, secreted proteins involved in determined using assays known in the blood-related disorders, H1305 (MCP-2) biological processes ranging from art: Methods in molecular Biology, viral infection, HIV, hemotopoiesis, anglogenesis, and 2000, vol. 138: Chemokine wound healing, cancer leukocyte trafficking. Members of this Protocols, Edited by A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq Accession WO9712914 Chemokines are a family of related Chemokine activities can be Inflammatory and eosinocyte CC W14990 small, secreted proteins involved in determined using assays known in the immune disorders type chemokine biological processes ranging from art: Methods in molecular Biology, eotaxin hemotopoiesis, anglogenesis, and 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols, Edited by A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human thymus GeneSeq Accession WO9711969 Chemokines are a family of related Chemokine activities can be Inflammatory and and activation W14018 small, secreted proteins involved in determined using assays known in the immune disorders regulated biological processes ranging from art: Methods in molecular Biology, cytokine hemotopoiesis, anglogenesis, and 2000, vol. 138: Chemokine (TARC) leukocyte trafficking. Members of this Protocols, Edited by A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq Accession WO9712041 Chemokines are a family of related Chemokine activities can be Cancer, would healing, chemokine beta- W16315 small, secreted proteins involved in determined using assays known in the immune disorders 8 short forms biological processes ranging from art: Methods in molecular Biology, hemotopoiesis, anglogenesis, and 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols, Edited by A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Microphage GeneSeq Accession WO9640923 Chemokines are a family of related Chemokine activities can be Inflammatory derived W20058 small, secreted proteins involved in determined using assays known in diseases, wound chemokine, MDC biological processes ranging from the art: Methods in Molecular healin, hermaatopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine angiogenesis leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO9844117 Chemokines are a family of related Chemokine activities can be Inflammatory and ZSIG-35 W30565 small, secreted proteins involved in determined using assays known in immune diseases biological processes ranging from the art: Methods in Molecular hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Primate CC GeneSeq Accesssion WO98328658 Chemokines are a family of related Chemokine activities can be Immune and chemokine W69990 small, secreted proteins involved in determined using assays known in inflammatory “ILINCK” biological processes ranging from the art: Methods in Molecular disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine abnormal leukocyte trafficking. Protocols. Edited by: A. E. I. Prodfoot, proliferation, T. N. C. Wells, and C. A. Power. regeneration,  ©Humana Press Inc., generation and Totowa, NJ atrophy disorders Primate CXC GeneSeq Accession WO9832858 Chemokines are a family of related Chemokine activities can be Immune and chemokine W69989 small, secreted proteins involved in determined using assays known in inflammatory “IBICK” biological processes ranging from the art: Methods in Molecular disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine abnormal leukocyte trafficking. Members of this Protocols. Editd by: A. E. I. Proudfoot, proliferation, family are involved in a similarly T. N. C. Wells, and C. A. Power. regeneration, diverse range of pathologies including  ©Humana Press Inc., generation and inflammation, allergy, tissue rejection, Totowa, NJ atrophy disorders viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CC-type GeneSeq Accession WO9831809 Chemokines are a family of related Chemokine activities can be Immune, chemokine protein W69163 small, secreted proteins involved in determined using assays known in inflammatory, and designated SLC biological processes ranging from the art: Methods in Molecular infectious (secondary hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine disorders, cancer lymphoid leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, chemokine) family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CC GeneSeq Accession WO9826071 Chemokines are a family of related Chemokine activities can be Cancer and chemokine ELC W62542 small, secreted proteins involved in determined using assays known in infectious protein biological processes ranging from the art: Methods in Molecular diseases, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine particularly leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, herpes virus family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human DVic-1 GeneSeq Accession Wo9823750 Chemokines are a family of related Chemokine activities can be Abnormal C-C chemokine W60649 small, secreted proteins involved in determined using assays known in proliferation, biological processes ranging from the art: Methods in Molecular regeneration, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine degeneration, and leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, atrophy disorders, family are involved in a similarly T. N. C. Wells, and C. A. Power. including cancer diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human C-C GeneSeq Accession WO9823750 Chemokines are a family of related Chemokine activities can be Immune chemokine W60650 small, secreted proteins involved in determined using assays known in disorders, cell DGWCC biological processes ranging from the art: Methods in Molecular proliferation hematophoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine disorders, cancer leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identifed. Human STCP-1 GeneSeq Accession WO9824907 Chemokines are a family of related Chemokine activities can be Immune W62783 small, secreted proteins involved in determined using assays known in disorders, biological processes ranging from the art: Methods in Molecular particularly T cell hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine related disorders, leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, viral infection, family are involved in a similarly T. N. C. Wells, and C. A. Power. and inflammation, diverse range of pathologies including  ©Humana Press Inc., especially joint inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Exodua protein GeneSeq Accession WO9821330 Chamokines are a family of related Chemokine activities can be Immune and W61279 small, secreted proteins involved in determined using assays known in inflammatory biological processes ranging from the art: Methods in Molecular disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine angiogenesis, leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, cancer, and family are involved in a similarly T. N. C. Wells, and C. A. Power. proliferation diverse range of pathologies including  ©Humana Press Inc., disorders, inflammation, allergy, tissue rejection, Totowa, NJ particularly viral infection, and tumor biology. The myeloproliferative chemokines exert their effects by acting diseases on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq Acession WO9814581 Chemokines are a family of related Chemokine activities can be Cancer and degenerative Chr19Kine W50887 small, secreted proteins involved in determined using assays known in disorders protein biological processes ranging from the art: Methods in Molecular hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: leukocyte trafficking. Members of this Chemokine Protocols, Edited by: family are involved in a similarly A. E. I. Proudfoot, T. N. C. Wells, and diverse range of pathologies including C. A. Power.  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human T cell GeneSeq Accession U.S. Pat. No. 5,780,268 Chemokines area family of related Chemokine activities can be Immune, inflammatory, mixed W58703 small, secreted proteins involved in determined using assays known in the and infectious disorders, lymphocyte biological processes ranging from art: Mehtods of Molecular Biology, cancer reaction hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine expressed leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, chemokine family are involved in a similarly T. N. C. Wells, and C. A. Power (TMEC) diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human 6CKine GeneSeq Accession W09814581 Chemokines area family of related Chemokine activities can be Cancer and degenerative protein W50885 small, secreted proteins involved in determined using assays known in the disorders biological processes ranging from art: Mehtods of Molecular Biology, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. human liver and GeneSeq Accession WO9817800 Chemokines area family of related Chemokine activities can be Immune, inflammatory, activation W57475 small, secreted proteins involved in determined using assays known in the and infectious disorders, regulated biological processes ranging from art: Mehtods of Molecular Biology, cancer chemokine hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine (LARC) leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES GeneSeq Accession WO9744462 Chemokines area family of related Chemokine activities can be Infectious diseases, peptide W29538 small, secreted proteins involved in determined using assays known in the particularly HIV biological processes ranging from art: Mehtods of Molecular Biology, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES 8-68 GeneSeq Accession WO9744462 Chemokines area family of related Chemokine activities can be Infectious diseases, W29529 small, secreted proteins involved in determined using assays known in the particularly HIV biological processes ranging from art: Mehtods of Molecular Biology, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES 9-68 GeneSeq Accession WO9744462 Chemokines area family of related Chemokine activities can be Infectious diseases, W29528 small, secreted proteins involved in determined using assays known in the particularly HIV biological processes ranging from art: Mehtods of Molecular Biology, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq Accession WO9811226 Chemokines area family of related Chemokine activities can be Abnormal proliferation, chemokine W59433 small, secreted proteins involved in determined using assays known in the regeneration, protein 331D5 biological processes ranging from art: Mehtods of Molecular Biology, degeneration or atrophy, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine including cancer leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq Accession WO9811226 Chemokines area family of related Chemokine activities can be Abnormal proliferation, chemokine W59430 small, secreted proteins involved in determined using assays known in the regeneration, protein 61164 biological processes ranging from art: Mehtods of Molecular Biology, degeneration or atrophy, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine including cancer leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq Accession WO9809171 Chemokines area family of related Chemokine activities can be Immune, Inflammatory, MCP-4 W56690 small, secreted proteins involved in determined using assays known in the and infectious diseases biological processes ranging from art: Mehtods of Molecular Biology, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human stromal GeneSeq Accession FR2751658 Chemokines are a family of related Chemokine activities can be HIV infections cell-derived W50766 small, secreted proteins involved in determined using assays known in chemokine, SDF-1 biological processes ranging from the art: Methods in Molecular hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Thymus expressed GeneSeq Accession WO9801557 Chemokines are a family of related Chemokine activities can be Immune and chemokine W44397 small, secreted proteins involved in determined using assays known in the inflammatory disorders (TECK) biological processes ranging from art: Methods in Molecular Biology, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarly and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO9801557 Chemokines are a family of related Chemokine activities can be Immune and MIP-3alpha W44398 small, secreted proteins involved in determined using assays known in the inflammatory disorders biological processes ranging from art: Methods in Molecular Biology, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarly and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO9801557 Chemokines are a family of related Chemokine activities can be Immune and MIP-3beta W44399 small, secreted proteins involved in determined using assays known in the inflammatory disorders biological processes ranging from art: Methods in Molecular Biology, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarly and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human monocyte GeneSeq Accession WO9802459 Chemokines are a family of related Chemokine activities can be Immune disorders, chemotactic W42072 small, secreted proteins involved in determined using assays known in the respiratory disorders, proprotein (MCPP) biological processes ranging from art: Methods in Molecular Biology, cancer sequence hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarly and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage- GeneSeq Accessions U.S. Pat. No. 5,688,927/ Chemokines are a family of related Chemokine activities can be Immune, and derived chemokine W40811 and U.S. Pat. No. 5,932,703 small, secreted proteins involved in determined using assays known in the inflammatory disorders, (MDC) Y24414 biological processes ranging from art: Methods in Molecular Biology, cancer hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarly and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage GeneSeq Accession U.S. Pat. No. 5,932,703 Chemokines are a family of related Chemokine activities can be Immune and derived chemokine Y24416 small, secreted proteins involved in determined using assays known in the inflammatory disorders analogue MDC- biological processes ranging from art: Methods in Molecular Biology, eyfy hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarly and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage GeneSeq Accession U.S. Pat. No. 5,932,703 Chemokines are a family of related Chemokine activities can be Immune and derived chemokine Y24413 small, secreted proteins involved in determined using assays known in the inflammatory disorders analogue MDC biological processes ranging from art: Methods in Molecular Biology, (n + 1) hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarly and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage GeneSeq Accession U.S. Pat. No. 5,932,703 Chemokines are a family of related Chemokine activities can be Immune and derived chemokine Y24415 small, secreted proteins involved in determined using assays known in the inflammatory disorders analogue MDC-yl biological processes ranging from art: Methods in Molecular Biology, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarly and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human type CC GeneSeq Accession JP11243960 Chemokines are a family of related Chemokine activities can be Allergic diseases and chemokine eotaxin Y43178 small, secreted proteins involved in determined using assays known in the HIV infection 3 protein sequence biological processes ranging from art: Methods in Molecular Biology, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarly and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human MCP-3 GeneSeq Acession WO9946392 Chemokines are a family of related Chemokine activities can be Cancer and immune and human Muc-1 Y29893 small, secreted proteins involved in determined using assays known in disorders, particularly core epitope biological processes ranging from the art: Methods in Molecular HIV infection (VNT) fusion hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine protein leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarily T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human IP-10 and GeneSeq Accession WO9946392 Chemokines are a family of related Chemokine activities can be Cancer and immune human Muc-1 core Y29894 small, secreted proteins involved in determined using assays known in the disorders, particularly epitope (VNT) biological processes ranging from art: Methods in Molecular Biology, HIV infection fusion protein hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarily and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human IP-10 and GeneSeq Accession W09946392 Chemokines are a family of related Chemokine activities can be Cancer and immune HIV-1 gp 120 Y29897 small, secreted proteins involved in determined using assays known in the disorders, particularly hypervariable biological processes ranging from art: Methods in Molecular Biology, HIV infection region fusion hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. protein leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarily and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human mammary GeneSeq Accessions WO9936540 Chemokines are a family of related Chemokine activities can be Breast disease, associated Y29092 and small, secreted proteins involved in determined using assays known in the including cancer chemokine Y29093 biological processes ranging from art: Methods in Molecular Biology, (MACK) protein hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. Full-Length and leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, Mature family are involved in a similarily and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Tim-1 protein GeneSeq Accession WO9933990 Chemokines are a family of related Chemokine activities can be Inflammation due to Y28290 small, secreted proteins involved in determined using assays known in the stimuli such as heart biological processes ranging from art: Methods in Molecular Biology, attacks and stroke, hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. infection, physical leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, trauma, UV or ionizing family are involved in a similarily and C. A. Power.  ©Humana radiation, burns, diverse range of pathologies including Press Inc., Totowa, NJ frostbite or corrosive inflammation, allergy, tissue rejection, chemicals viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human Lkn-1 GeneSeq Accessions WO9928473 and Chemokines are a family of related Chemokine activities can be HIV infection and Full-Length and Y17280, Y17274, WO9928472 small, secreted proteins involved in determined using assays known in the cancer, particularly Mature protein Y17281, and biological processes ranging from art: Methods in Molecular Biology, leukemia Y17275 hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarily and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq Accession WO9920759 Chemokines are a family of related Chemokine activities can be Inhibit or stimulate modified Y05818 small, secreted proteins involved in determined using assays known in the angiogenesis, inhibit the chemokine met- biological processes ranging from art: Methods in Molecular Biology, binding of HIV hSDF-1 alpha hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, family are involved in a similarily and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq Accession WO9920759 Chemokines are a family of related Chemokine activities can be Inhibit or stimulate modified Y05819 small, secreted proteins involved in determined using assays known in the angiogenesis, inhibit the chemokine met- biological processes ranging from art: Methods in Molecular Biology, binding of HIV, hSDF-1 beta hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. antiinflammatory; leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, immunosuppressant family are involved in a similarily and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq Accession WO9920759 Chemokines are a family of related Chemokine activities can be Inhibit or stimulate modified Y05820 small, secreted proteins involved in determined using assays known in the angiogenesis, inhibit the chemokine biological processes ranging from art: Methods in Molecular Biology, binding of HIV, GroHEK/hSDF- hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. antiinflammatory; 1alpha leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, immunosuppressant family are involved in a similarily and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq Accession WO9920759 Chemokines are a family of related Chemokine activities can be Inhibit or stimulate modified Y05821 small, secreted proteins involved in determined using assays known in the angiogenesis, inhibit the chemokine biological processes ranging from art: Methods in Molecular Biology, binding of HIV, GroHEK/hSDF- hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine Protocols. antiinflammatory; 1beta. leukocyte trafficking. Members of this Edited by: A. E. I. Proudfoot, T. N. C. Wells, immunosuppressant family are involved in a similarily and C. A. Power.  ©Humana diverse range of pathologies including Press Inc., Totowa, NJ inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq Accession WO9912968 Chemokines are a family of related Chemokine activities can be Increase or enhance an Eotaxin Y14230 small, secreted proteins involved in determined using assays known in inflammatory response, biological processes ranging from the art: Methods in Molecular an immune response hematopoiesis, agiogenesis, and Bilogy, 2000, vol. 138: Chemokine orhaematopoietic cell- leukocye trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, associated activity; treat family are involved in a similarly T. N. C. Wells, and C. A. Power. a vascular indication; diverse range of pathologies including  ©Humana Press Inc., Cancer; enhance wound inflammation, allergy, tissue rejection, Totowa, NJ healing, to prevent or viralk infection, and tumor biology. The treat asthma, organ chemokines exert their effects by acting transplant rejction, on a family of seven transmembrane G- rheumatoid arthritis or protein-coupled receptors. Over 40 allergy human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq Accession WO9912968 Chemokines are a family of related Chemokine activities can be Immune disorders, hMCP1a Y14225 small, secreted proteins involved in determined using assays known in Vascular disorders, biological processes ranging from the art: Methods in Molecular Wound healing, cancer, hematopoiesis, agiogenesis, and Bilogy, 2000, vol. 138: Chemokine prevent organ transplant leukocye trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, rejection, Increase or family are involved in a similarly T. N. C. Wells, and C. A. Power. enhance an diverse range of pathologies including  ©Humana Press Inc., inflammatory response, inflammation, allergy, tissue rejection, Totowa, NJ viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq Accession WO9912968 Chemokines are a family of related Chemokine activities can be Immune disorders, hMCP1b Y14226 small, secreted proteins involved in determined using assays known in Vascular disorders, biological processes ranging from the art: Methods in Molecular Wound healing, cancer, hematopoiesis, agiogenesis, and Bilogy, 2000, vol. 138: Chemokine prevent organ transplant leukocye trafficking: Members of this Protocols. Edited by: A. E. I. Proudfoot, rejection, Increase or family are involved in a similarly T. N. C. Wells, and C. A. Power. enhance an diverse range of pathologies including  ©Humana Press Inc., inflammatory response, inflammation, allergy, tissue rejection, Totowa, NJ viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq Accession WO9912968 Chemokines are a family of related Chemokine activities can be Immune disorders, hSDF1b Y14228 small, secreted proteins involved in determined using assays known in Vascular disorders, biological processes ranging from the art: Methods in Molecular Wound healing, cancer, hematopoiesis, agiogenesis, and Bilogy, 2000, vol. 138: Chemokine prevent organ transplant leukocye trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, rejection, Increase or family are involved in a similarly T. N. C. Wells, and C. A. Power. enhance an diverse range of pathologies including  ©Humana Press Inc., inflammatory response, inflammation, allergy, tissue rejection, Totowa, NJ viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq Accession WO9912968 Chemokines are a family of related Chemokine activities can be Immune disorders, hIL-8 Y14229 small, secreted proteins involved in determined using assays known in Vascular disorders, biological processes ranging from the art: Methods in Molecular Wound healing, cancer, hematopoiesis, agiogenesis, and Bilogy, 2000, vol. 138: Chemokine prevent organ transplant leukocye trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, rejection, Increase or family are involved in a similarly T. N. C. Wells, and C. A. Power. enhance an diverse range of pathologies including  ©Humana Press Inc., inflammatory response, inflammation, allergy, tissue rejection, Totowa, NJ; and Holmes et al (1991) viralk infection, and tumor biology. The Science 253, 1278-80. chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq Accession WO9912968 Chemokines are a family of related Chemokine activities can be Immune disorders, hMCP1 Y14222 small, secreted proteins involved in determined using assays known in Vascular disorders, biological processes ranging from the art: Methods in Molecular Wound healing, cancer, hematopoiesis, agiogenesis, and Bilogy, 2000, vol. 138: Chemokine prevent organ transplant leukocye trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, rejection, Increase or family are involved in a similarly T. N. C. Wells, and C. A. Power. enhance an diverse range of pathologies including  ©Humana Press Inc., inflammatory response, inflammation, allergy, tissue rejection, Totowa, NJ viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq Accession WO9912968 Chemokines are a family of related Chemokine activities can be Immune disorders, hMCP2 Y14223 small, secreted proteins involved in determined using assays known in Vascular disorders, biological processes ranging from the art: Methods in Molecular Wound healing, cancer, hematopoiesis, agiogenesis, and Bilogy, 2000, vol. 138: Chemokine prevent organ transplant leukocye trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, rejection, Increase or family are involved in a similarly T. N. C. Wells, and C. A. Power. enhance an diverse range of pathologies including  ©Humana Press Inc., inflammatory response, inflammation, allergy, tissue rejection, Totowa, NJ viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq Accession WO9912968 Chemokines are a family of related Chemokine activities can be Immune disorders, hMCP3 Y14224 small, secreted proteins involved in determined using assays known in Vascular disorders, biological processes ranging from the art: Methods in Molecular Wound healing, cancer, hematopoiesis, agiogenesis, and Bilogy, 2000, vol. 138: Chemokine prevent organ transplant leukocye trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, rejection, Increase or family are involved in a similarly T. N. C. Wells, and C. A. Power. enhance an diverse range of pathologies including  ©Humana Press Inc., inflammatory response, inflammation, allergy, tissue rejection, Totowa, NJ viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. C-C chemokine, GeneSeq Accession EP905240 Chemokines are a family of related Chemokine activities can be Inflammatory, Immune MCP2 Y05300 small, secreted proteins involved in determined using assays known in and infectious diseases; biological processes ranging from the art: Methods in Molecular pulmonary diseases and hematopoiesis, agiogenesis, and Bilogy, 2000, vol. 138: Chemokine skin disorders; tumours, leukocye trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, and angiogenesis-and family are involved in a similarly T. N. C. Wells, and C. A. Power. haematopoiesis-related diverse range of pathologies including  ©Humana Press Inc., diseases inflammation, allergy, tissue rejection, Totowa, NJ viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Wild type GeneSeq Accession EP906954 Chemokines are a family of related Chemokine activities can be Inflammatory, Immume monocyte Y07233 small, secreted proteins involved in determined using assays known in and infectious diseases; chemotactic biological processes ranging from the art: Methods in Molecular pulmonary diseases and protein 2 hematopoiesis, agiogenesis, and Bilogy, 2000, vol. 138: Chemokine skin disorders; tumours, leukocye trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, and angiogenesis-and family are involved in a similarly T. N. C. Wells, and C. A. Power. haematopoiesis-related diverse range of pathologies including  ©Humana Press Inc., diseases inflammation, allergy, tissue rejection, Totowa, NJ viralk infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Truncated GeneSeq Accession EP906954 Chemokines area family of related small, Chemokines activities can be Inflammatory, immune monocyte Y07234 secreted proteins involved in biological determined using assays known in the and infectious diseases; chemotactic processes ranging from hematopoiesis, art: Methods in Molecular Biology, pulmonry diseases and protein 2 (6-76) angiogenesis, and leukocyte trafficking. 2000, vol. 138: Chemokine skin disorders; tumours, Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, and angiogenesis-and similarly diverse range of pathologies T. N. C. Wells, and C. A. Power, haematopoiesis-related including inflammation, allergy, tissue Humana Press Inc., Totowa, diseases rejection, viral infection, and tumor NJ biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Truncated GeneSeq Accessions EP905241; Chemokines area family of related small, Chemokines activities can be Inflammatory, immune RANTES Y07236 and EP906954 secreted proteins involved in biological determined using assays known in the and infectious diseases; protein (3-68) Y07232 processes ranging from hematopoiesis, art: Methods in Molecular Biology, pulmonry diseases and angiogenesis, and leukocyte trafficking. 2000, vol. 138: Chemokine skin disorders; tumours, Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, and angiogenesis-and similarly diverse range of pathologies T. N. C. Wells, and C. A. Power, haematopoiesis-related including inflammation, allergy, tissue Humana Press Inc., Totowa, diseases rejection, viral infection, and tumor NJ biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Wild type GeneSeq Accession EP905241 Chemokines area family of related small, Chemokines activities can be Inflammatory, immune monocyte Y07237 secreted proteins involved in biological determined using assays known in the and infectious diseases; chemotactic processes ranging from hematopoiesis, art: Methods in Molecular Biology, pulmonry diseases and protein 2 angiogenesis, and leukocyte trafficking. 2000, vol. 138: Chemokine skin disorders; tumours, Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, and angiogenesis-and similarly diverse range of pathologies T. N. C. Wells, and C. A. Power, haematopoiesis-related including inflammation, allergy, tissue Humana Press Inc., Totowa, diseases rejection, viral infection, and tumor NJ biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Truncated GeneSeq Accession EP905241 Chemokines area family of related small, Chemokines activities can be Inflammatory, immune monocyte Y07238 secreted proteins involved in biological determined using assays known in the and infectious diseases; chemotactic processes ranging from hematopoiesis, art: Methods in Molecular Biology, pulmonry diseases and protein 2 (6-76) angiogenesis, and leukocyte trafficking. 2000, vol. 138: Chemokine skin disorders; tumours, Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, and angiogenesis-and similarly diverse range of pathologies T. N. C. Wells, and C. A. Power, haematopoiesis-related including inflammation, allergy, tissue Humana Press Inc., Totowa, diseases rejection, viral infection, and tumor NJ biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A partial GeneSeq Accession EP897980 Chemokines area family of related small, Chemokines activities can be Soluble CXCR4B CXCR4B W97363 secreted proteins involved in biological determined using assays known in the receptor polypeptides protein processes ranging from hematopoiesis, art: Methods in Molecular Biology, may be useful for angiogenesis, and leukocyte trafficking. 2000, vol. 138: Chemokine inhibiting chemokine Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, activities and viral similarly diverse range of pathologies T. N. C. Wells, and C. A. Power, infection. including inflammation, allergy, tissue Humana Press Inc., Totowa, rejection, viral infection, and tumor NJ biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Interferon GeneSeq Accession U.S. Pat. No. 5,871,723 Chemokines area family of related small, Chemokines activities can be Angiogenesis, Cancer, gamma- W96709 secreted proteins involved in biological determined using assays known in the Inflammatory and inducible processes ranging from hematopoiesis, art: Methods in Molecular Biology, Immune disorders, protein (IP-10) angiogenesis, and leukocyte trafficking. 2000, vol. 138: Chemokine Cardio-Vascular Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, discorders, Musco- similarly diverse range of pathologies T. N. C. Wells, and C. A. Power, skeletal disorders including inflammation, allergy, tissue Humana Press Inc., Totowa, rejection, viral infection, and tumor NJ biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A monokine GeneSeq Accession U.S. Pat. No. 5,871,723 Chemokines area family of related small, Chemokines activities can be Angiogenesis, Cancer, induced by W96710 secreted proteins involved in biological determined using assays known in the Inflammatory and gamma- processes ranging from hematopoiesis, art: Methods in Molecular Biology, Immune disorders, interferon angiogenesis, and leukocyte trafficking. 2000, vol. 138: Chemokine Cardio-Vascular (MIG) Members of this family are involved in a Protocols. Edited by: A. E. I. Prougfoot; discorders, Musco- similarly diverse range of pathologies T. N. C. Wells, and C. A. Power, skeletal disorders including inflammation, allergy, tissue Humana Press Inc., Totowa, rejection, viral infection, and tumor NJ biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Interleukin-8 GeneSeq Accession U.S. Pat. No. 5,871,723 Chemokines area family of related small, Chemokines activities can be Angiogenesis, Cancer, (IL-8) protein. W96711 secreted proteins involved in biological determined using assays known in the Inflammatory and processes ranging from hematopoiesis, art: Methods in Molecular Biology, Immune disorders, angiogenesis, and leukocyte trafficking. 2000, vol. 138: Chemokine Cardio-Vascular Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, discorders, Musco- similarly diverse range of pathologies T. N. C. Wells, and C. A. Power, skeletal disorders including inflammation, allergy, tissue Humana Press Inc., Totowa, rejection, viral infection, and tumor NJ; and Holmes et al (1991) Science biology. The chemokines exert their 253, 1278-80. effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Epithelial GeneSeq Accession U.S. Pat. No. 5,871,723 Chemokines area family of related small, Chemokines activities can be Angiogenesis, Cancer, neutrophil W96712 secreted proteins involved in biological determined using assays known in the Inflammatory and activating processes ranging from hematopoiesis, art: Methods in Molecular Biology, Immune disorders, protein-78 angiogenesis, and leukocyte trafficking. 2000, vol. 138: Chemokine Cardio-Vascular (ENA-78) Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, discorders, Musco- similarly diverse range of pathologies T. N. C. Wells, and C. A. Power, skeletal disorders including inflammation, allergy, tissue Humana Press Inc., Totowa, rejection, viral infection, and tumor NJ biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Growth related GeneSeq Accession U.S. Pat. No. 5,871,723 Chemokines area family of related small, Chemokines activities can be Angiogenesis, Cancer, oncogene-alpha W96713 secreted proteins involved in biological determined using assays known in the Inflammatory and (GRO-alpha). processes ranging from hematopoiesis, art: Methods in Molecular Biology, Immune disorders, angiogenesis, and leukocyte trafficking. 2000, vol. 138: Chemokine Cardio-Vascular Members of this family are involved in a Protocols. Edited by: A. E. I. Proudfoot, discorders, Musco- similarly diverse range of pathologies T. N. C. Wells, and C. A. Power, skeletal disorders including inflammation, allergy, tissue Humana Press Inc., Totowa, rejection, viral infection, and tumor NJ biology. The chemokines exert their effects by acting on a fmaily of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Growth related GeneSeq Accession U.S. Pat. No. 5,871,723 Chemokines are a family of related Chemokine activities can be Angiogenesis, Cancer, oncogene-beta W96714 small, secreted proteins involved in determined using assays known in Inflammatory and (GRO-beta). biological processes ranging from the art: Methods in Molecular Immune disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine Cardio-Vascular leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco- family are involved in a similarly T. N. C. Wells, and C. A. Power, skeletal disorders diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified Growth related GeneSeq Accession U.S. Pat. No. 5,871,723 Chemokines are a family of related Chemokine activities can be Angiogenesis, Cancer, oncogene-gamma W96715 small, secreted proteins involved in determined using assays known in Inflammatory and (GRO-gamma) biological processes ranging from the art: Methods in Molecular Immune disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine Cardio-Vascular leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco- family are involved in a similarly T. N. C. Wells, and C. A. Power, skeletal disorders diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A platelet basic GeneSeq Accession U.S. Pat. No. 5,871,723 Chemokines are a family of related Chemokine activities can be Angiogenesis, Cancer, protein (PBP) W96716 small, secreted proteins involved in determined using assays known in Inflammatory and biological processes ranging from the art: Methods in Molecular Immune disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine Cardio-Vascular leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco- family are involved in a similarly T. N. C. Wells, and C. A. Power, skeletal disorders diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Connective tissue GeneSeqAccession U.S. Pat. No. 5,871,723 Chemokines are a family of related Chemokine activities can be Angiogenesis, Cancer, activating protein- S96717 small, secreted proteins involved in determined using assays known in Inflammatory and III (CTAP-III) biological processes ranging from the art: Methods in Molecular Immune disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine Cardio-Vascular leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco- family are involved in a similarly T. N. C. Wells, and C. A. Power, skeletal disorders diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Beta- GeneSeq Accession U.S. Pat. No. 5,871,723 Chemokines are a family of related Chemokine activities can be Angiogenesis, Cancer, thromboglobulin W96718 small, secreted proteins involved in determined using assays known in Inflammatory and protein (beta-TG) biological processes ranging from the art: Methods in Molecular Immune disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine Cardio-Vascular leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco- family are involved in a similarly T. N. C. Wells, and C. A. Power, skeletal disorders diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Neutrophil GeneSeq Accession U.S. Pat. No. 5,871,723 Chemokines are a family of related Chemokine activities can be Angiogenesis, Cancer, activating peptide- W96719 small, secreted proteins involved in determined using assays known in Inflammatory and 2 (NAP-2) biological processes ranging from the art: Methods in Molecular Immune disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine Cardio-Vascular leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco- family are involved in a similarly T. N. C. Wells, and C. A. Power, skeletal disorders diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Granulocyte GeneSeq Accession U.S. Pat. No. 5,871,723 Chemokines are a family of related Chemokine activities can be Angiogenesis, Cancer, chemotactic W96720 small, secreted proteins involved in determined using assays known in Inflammatory and protein-2 (GCP-2) biological processes ranging from the art: Methods in Molecular Immune disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine Cardio-Vascular leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, disorders, Musco- family are involved in a similarly T. N. C. Wells, and C. A. Power, skeletal disorders diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession EP887409 Chemokines are a family of related Chemokine activities can be Immune disorders, viral, MIG-beta protein W90124 small, secreted proteins involved in determined using assays known in parasitic, fungal or biological processes ranging from the art: Methods in Molecular bacterial infections, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine Cancer; autoimmune leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, diseases or transplant family are involved in a similarly T. N. C. Wells, and C. A. Power, rejection diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human ZCHEMO-8 GeneSeq Accession WO9854326 Chemokines are a family of related Chemokine activities can be Immune disorders, W82716 small, secreted proteins involved in determined using assays known in cancer, myelopoietic biological processes ranging from the art: Methods in Molecular disorders, autoimmune hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine disorders and leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, immunodeficiencies, family are involved in a similarly T. N. C. Wells, and C. A. Power, Inflammatory and diverse range of pathologies including  ©Humana Press Inc., infectious diseases, inflammation, allergy, tissue rejection, Totowa, NJ Vascular disorders, viral infection, and tumor biology. The wound healing chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human Act-2 GeneSeq Accession WO9854326 Chemokines are a family of related Chemokine activities can be Immune disorders, protein W82717 small, secreted proteins involved in determined using assays known in cancer, myelopoietic biological processes ranging from the art: Methods in Molecular disorders, autoimmune hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine disorders and leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, immunodeficiencies, family are involved in a similarly T. N. C. Wells, and C. A. Power, Inflammatory and diverse range of pathologies including  ©Humana Press Inc., infectious diseases, inflammation, allergy, tissue rejection, Totowa, NJ Vascular disorders, viral infection, and tumor biology. The wound healing chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human SISD GeneSeq Acession WO9854326 Chemokines are a family of related Chemokine activities can be Immune disorders, protein W82720 small, secreted proteins involved in determined using assays known in cancer, myelopoietic biological processes ranging from the art: Methods in Molecular disorders, autoimmune hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: disorders and leukocyte trafficking. Members of this Chemokine Protocols, Edited by: immunodeficiencies, family are involved in a similarly A. E. I. Proudfoot, T. N. C. Wells, and Inflammatory and diverse range of pathologies including C. A. Power.  ©Humana Press Inc., infectious diseases, inflammation, allergy, tissue rejection, Totowa, NJ Vascular disorders, viral infection, and tumor biology. The wound healing chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human M110 GeneSeq Accession WO9854326 Chemokines area family of related Chemokine activities can be Immune disorders, protein W82721 small, secreted proteins involved in determined using assays known in the cancer, myelopoietic biological processes ranging from art: Mehtods of Molecular Biology, disorders, autoimmune hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine disorders and leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, immunodeficiencies, family are involved in a similarly T. N. C. Wells, and C. A. Power Inflammatory and diverse range of pathologies including  ©Humana Press Inc., Totowa, infectious diseases, inflammation, allergy, tissue rejection, NJ Vascular disorders, viral infection, and tumor biology. The wound healing chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human M11A GeneSeq Accession WO9854326 Chemokines area family of related Chemokine activities can be Immune disorders, protein W82722 small, secreted proteins involved in determined using assays known in the cancer, myelopoietic biological processes ranging from art: Mehtods of Molecular Biology, disorders, autoimmune hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine disorders and leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, immunodeficiencies, family are involved in a similarly T. N. C. Wells, and C. A. Power Inflammatory and diverse range of pathologies including  ©Humana Press Inc., Totowa, infectious diseases, inflammation, allergy, tissue rejection, NJ Vascular disorders, viral infection, and tumor biology. The wound healing chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CCC3 GeneSeq Accession WO9854326 Chemokines area family of related Chemokine activities can be Immune disorders, protein W82723 small, secreted proteins involved in determined using assays known in the cancer, myelopoietic biological processes ranging from art: Mehtods of Molecular Biology, disorders, autoimmune hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine disorders and leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, immunodeficiencies, family are involved in a similarly T. N. C. Wells, and C. A. Power Inflammatory and diverse range of pathologies including  ©Humana Press Inc., Totowa, infectious diseases, inflammation, allergy, tissue rejection, NJ Vascular disorders, viral infection, and tumor biology. The wound healing chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A human L105 GeneSeq Accession WO9856818 Chemokines area family of related Chemokine activities can be Cancer, wound healing chemokine W87588 small, secreted proteins involved in determined using assays known in the designated biological processes ranging from art: Mehtods of Molecular Biology, huL105_3. hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A human L105 GeneSeq Accession WO9856818 Chemokines area family of related Chemokine activities can be Cancer, wound healing chemokine W87589 small, secreted proteins involved in determined using assays known in the designated biological processes ranging from art: Mehtods of Molecular Biology, huL105_7. hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human mature GeneSeq Accession WO9848828 Chemokines area family of related Chemokine activities can be Infectious diseases, gro-alpha W81498 small, secreted proteins involved in determined using assays known in the sepsis polypeptide biological processes ranging from art: Mehtods of Molecular Biology, used to treat hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine sepsis leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human mature GeneSeq Accession WO9848828 Chemokines area family of related Chemokine activities can be Infectious diseases, gro-gamma W81500 small, secreted proteins involved in determined using assays known in the sepsis polypeptide biological processes ranging from art: Mehtods of Molecular Biology, used to treat hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine sepsis leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human thymus GeneSeq Accessions WO0053635 Chemokines area family of related Chemokine activities can be Inflammatory disorders, expressed B19607 and small, secreted proteins involved in determined using assays known in the cancer, Immune and chemokine B19608 biological processes ranging from art: Mehtods of Molecular Biology, vascular disorders TECK and hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine TECK variant leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq Accession WO0042071 Chemokines area family of related Chemokine activities can be Autoimmune disorders, chemokine B15791 small, secreted proteins involved in determined using assays known in the Immune, Vascular and SDF1alpha biological processes ranging from art: Mehtods of Molecular Biology, Inflammatory disorders hematopoiesis, angiogenesis, and 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power diverse range of pathologies including  ©Humana Press Inc., Totowa, inflammation, allergy, tissue rejection, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, GROalpha B15793 small, secreted proteins involved in determined using assasys known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory diorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, eotaxin B15794 small, secreted proteins involved in determined using assasys known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, MIG B15803 small, secreted proteins involved in determined using assasys known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, PF4 B15804 small, secreted proteins involved in determined using assasys known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, I-309 B15805 small, secreted proteins involved in determined using assasys known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, HCC-1 B15806 small, secreted proteins involved in determined using assasys known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, C10 B15807 small, secreted proteins involved in determined using assasys known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, CCR-2 B15808 small, secreted proteins involved in determined using assasys known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, ENA-78 B15809 small, secreted proteins involved in determined using assasys known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, GRObeta B15810 small, secreted proteins involved in determined using assasys known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot; family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, IP-10 B15811 small, secreted proteins involved in determined using assays known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, SDF1beta B15812 small, secreted proteins involved in determined using assays known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, GRO alpha B15813 small, secreted proteins involved in determined using assays known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession WO0042071 Chemokines are a family of related Chemokine activities can be Autoimmune disorders, MIP1beta B15831 small, secreted proteins involved in determined using assays known in Immune, Vascular and biological processes ranging from the art: Methods in Molecular Inflammatory disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A human C-C GeneSeq Accession U.S. Pat. No. 6,096,300 Chemokines are a family of related Chemokine activities can be Cancer chemokine B07939 small, secreted proteins involved in determined using assays known in designated exodus biological processes ranging from the art: Methods in Molecular hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession U.S. Pat. No. 6,084,071 Chemokines are a family of related Chemokine activities can be Chemotaxis, Gene L105_7 Y96922 small, secreted proteins involved in determined using assays known in Therapy, Wound biological processes ranging from the art: Methods in Molecular healing hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human chemokine GeneSeq Accession U.S. Pat. No. 6,084,071 Chemokines are a family of related Chemokine activities can be Chemotaxis, Gene L105_3 Y96923 small, secreted proteins involved in determined using assays known in Therapy, Wound biological processes ranging from the art: Methods in Molecular healing hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human secondary GeneSeq Accession WO0038706 Chemokines are a family of related Chemokine activities can be Cancer, Vascular and lymphoid B01434 small, secreted proteins involved in determined using assays known in Immune disorders chemokine (SLC) biological processes ranging from the art: Methods in Molecular hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human non-ELR GeneSeq Accession WO0029439 Chemokines are a family of related Chemokine activities can be Immune and CXC chemokine Y96310 small, secreted proteins involved in determined using assays known in Inflammatory disorders, H174 biological processes ranging from the art: Methods in Molecular Cancer, Haemostatic hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine and thrombolytic leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, activity family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human non-ELR GeneSeq Accession WO0029439 Chemokines are a family of related Chemokine activities can be Immune and CXC chemokine Y96311 small, secreted proteins involved in determined using assays known in Inflammatory disorders, IP10 biological processes ranging from the art: Methods in Molecular Cancer, haemostatic and hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine thrombolytic activity leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human non-ELR GeneSeq Accession WO0029439 Chemokines are a family of related Chemokine activities can be Immune and CXC chemokine Y96313 small, secreted proteins involved in determined using assays known in Inflammatory disorders, Mig biological processes ranging from the art: Methods in Molecular Cancer, haemostatic and hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine thrombolytic activity leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ^(~)17 receptors thus far identified. Human chemokine GeneSeq Accession WO0028035 Chemokines are a family of related Chemokine activities can be Cancer, wound healing, Ckbeta-7 Y96280 small, secreted proteins involved in determined using assays known in inflammatory and biological processes ranging from the art: Methods in Molecular immunoregulatory hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine disorders leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ^(~)17 receptors thus far identified. Human chemokine GeneSeq Accession WO0028035 Chemokines are a family of related Chemokine activities can be Cancer, wound healing, MIP-1alpha Y96281 small, secreted proteins involved in determined using assays known in inflammatory and biological processes ranging from the art: Methods in Molecular immunoregulatory hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine disorders leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ^(~)17 receptors thus far identified. Human mature GenSeq Accession WO0028035 Chemokines are a family of related Chemokine activities can be Cancer, wound healing, chemokine Y96282 small, secreted proteins involved in determined using assays known in inflammatory and Ckbeta-7 biological processes ranging from the art: Methods in Molecular immunoregulatory (optionally hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine disorders truncated) leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ^(~)17 receptors thus far identified. Human chemokine GeneSeq Accession WO0018431 Chemokines are a family of related Chemokine activities can be Soluble CXCR3 receptor CXCR3 Y79372 small, secreted proteins involved in determined using assays known in polypeptides may be biological processes ranging from the art: Methods in Molecular useful for inhibiting hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine chemokine activities leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, and viral infection. family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ^(~)17 receptors thus far identified. Human neurotactin GeneSeq Accession U.S. Pat. No. 6,043,086 Chemokines are a family of related Chemokine activities can be Neurological disorders, chemokine like Y53259 small, secreted proteins involved in determined using assays known in Immune and respiratory domain biological processes ranging from the art: Methods in Molecular disorders hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ^(~)17 receptors thus far identified. Human CC type GeneSeq Accession JP11302298 Chemokines are a family of related Chemokine activities can be Cancer and infectious chemokine Y57771 small, secreted proteins involved in determined using assays known in diseases interleukin C biological processes ranging from the art: Methods in Molecular hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ^(~)17 receptors thus far identified Human CKbeta-9 GeneSeq Accession U.S. Pat. No. 6,153,441 Chemokines are a family of related Chemokine activities can be Cancer, Auto-immune B50860 small, secreted proteins involved in determined using assays known in and inflammatory biological processes ranging from the art: Methods in Molecular disorders, hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: Chemokine Cardiovascular leukocyte trafficking. Members of this Protocols. Edited by: A. E. I. Proudfoot, disorders family are involved in a similarly T. N. C. Wells, and C. A. Power. diverse range of pathologies including  ©Humana Press Inc., inflammation, allergy, tissue rejection, Totowa, NJ viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein-coupled receptors. Over 40 human chemokines have been described, which bind to ^(~)17 receptors thus far identified Preproapolipoprotein GeneSeq Accession WO9637608 Apoa-1 participates in the reverse Lipid binding activity can be Useful for “paris” variant W08602 transport of cholesterol from tissues to determined using assays known in cardiovascular the liver for excretion by promoting the art, such as, for example, the disorders, cholesterol cholesterol efflux from tissues and by Cholesterol Efflux Assays of disorders, and acting as a cofactor for the lecithin Takahaski et al., P.N.A.S., Vol. 96, Hyperlipidaemia cholesterol acyltransferase (lcat). Issue 20, 11358-11363, Sep. 28, 1999. Preproapolipoprotein 5,721,114 Apoa-1 participates in the reverse Lipid binding activity can be Useful for “milano” variant transport of cholesterol from tissues to determined using assays known in cardiovascular the liver for excretion by promoting the art, such as, for example, the disorders, cholesterol cholesterol efflux from tissues and by Cholesterol Efflux Assays of disorders, and acting as a cofactor for the lecithin Takahaski et al., P.N.A.S., Vol. 96, Hyperlipidaemia cholesterol acyltransferase (lcat). Issue 20, 11358-11363, Sep. 28, 1999. Glycodelin-A; GeneSeq Accession WO9628169 Naturally produced female contraceptive Glycodelin-A activity can be Naturally derived Progesterone- W00289 that is removed rapidly from the body determined using the hemizona contraceptive useful for associated following 2-3 days production. Uses assay as described in Oehninger, S., the prevention of endometrial include contraception Coddington, C. C., Hodgen, G. D., pregnancy. protein and Seppala, M (1995) Fertil. Steril. 63, 377-383. NOGO-A Genbank Accession NOGO polypeptides are potent Inhibition of Neurite outgrowth. NOGO-A polypeptide CAB99248 inhibitors of neurite growth. Antagonists to NOGO polypeptides antagonists are useful may promote the outgrowth of for the promotion of neurites, thus inducing regeneration neural growth, which of neurons. could be useful in the treatment of neural disorders and dysfunction due to degenerative diseases or trauma; useful in the treatment of neoplastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. NOGO-B Genbank Accession NOGO polypeptides are potent Inhibition of Neurite outgrowth. NOGO-B polypeptide CAB99249 inhibitors of neurite growth. Antagonists to NOGO polypeptides antagonists are useful may promote the outgrowth of for the promotion of neurites, thus inducing regeneration neural growth, which of neurons. could be useful in the treatment of neural disorders and dysfunction due to degenerative diseases or trauma; useful in the treatment of neoplastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. NOGO-C Genbank Accession NOGO polypeptides are potent Inhibition of Neurite outgrowth. NOGO-C polypeptide CAB99250 inhibitors of neurite growth. Antagonists to NOGO polypeptides antagonists are useful may promote the outgrowth of for the promotion of neurites, thus inducing regeneration neural growth, which of neurons. could be useful in the treatment of neural disorders and dysfunction due to degenerative diseases or trauma; useful in the treatment of neoplastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. NOGO-66 Genbank Accession NOGO polypeptides are potent Inhibition of Neurite outgrowth by NOGO-66 receptor Receptor AAG53612 inhibitors of neurite growth, and are mediating the biological effects of polypeptides are useful thought to mediate their effects through NOGO polypeptides. Soluble for the promotion of the NOGO-66 Receptor. NOGO-66 receptor polypeptides neural growth, which may promote the outgrowth of could be useful in the neurites, thus inducing regeneration treatment of neural of neurons. disorders and dysfunction due to degenerative diseases or trauma; useful in the treatment of neoplastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. Antibodies specific U.S. Pat. No. 5,416,197 These antibodies are useful for the Collapsin activity, which is thought Useful for the for collapsin promotion of neurite outgrowth to inhibit the outgrowth of neurites, promotion of neural can be assayed in the presence of growth, which could be antibodies specific for collapsing useful in the treatment using assays known in the art, such of neural disorders and as, for example, the collapse assay dysfunction due to disclosed by Luo et al., Cell 1993 degenerative diseases or Oct. 22; 75(2): 217-27 trauma. Humanized Anti- WO9845331 These agents have anti-inflammatory VEGF activity can be determined Promotion of growth VEGF Antibodies, and anti-cancer applications using assays known in the art, such and proliferation of and fragments as those disclosed in International cells, such as vascular thereof Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti- angiogenic agents, and may be applicable for cancer Humanized Anti- WO0029584 These agents have anti-inflammatory VEGF activity can be determined Promotion of growth VEGF Antibodies, and anti-cancer applications using assays known in the art, such and proliferation of and fragments as those disclosed in International cells, such as vascular thereof Publication No. WO0045835, for endothelial cells. example. Antagonists may be useful as anti- angiogenic agents, and may be applicable for cancer Membrane bound GeneSeq. Accession WO9963088 Cancer, Immune Disorders These proteins can be used for Activities can be proteins Y66631-Y66765 linking bioactive molecules to cells determined using assay and for modulating biological known in the art, activities of cells, using the suchas, for example, the polypeptides for specific targeting. assays disclosed in The polypeptide targeting can be International used to kill the target cells, e.g. for Publication No. the treatment of cancers. These WO0121658. proteins are useful for the treatment of immune system disorders. Secreted and GenSeq Accession WO0053756 Cancer, Immune Disorders These proteins can be used for Activities can be Transmembrane B44241-B44334 linking bioactive molecules to cells determined using assay polypeptides and for modulating biological known in the art, activities of cells, using the suchas, for example, the polypeptides for specific targeting. assays disclosed in The polypeptide targeting can be International used to kill the target cells, e.g. for Publication No. the treatment of cancers. These WO0121658 proteins are useful for the treatment of immune system disorders. Secreted and GeneSeq Accession WO9946281 Cancer, Immune Disorders These proteins can be used for Activities can be Transmembrane Y41685-Y41774 linking bioactive molecules to cells determined using assay polypeptides and for modulating biological known in the art, activities of cells, using the suchas, for example, the polypeptides for specific targeting. assays disclosed in The polypeptide targeting can be International used to kill the target cells, e.g. for Publication No. the treatment of cancers. These WO0121658 proteins are useful for the treatment of immune system disorders.

Conjugation and Coupling

The present invention provides therapeutic agents comprising an ELP component and a therapeutic component, such as therapeutic proteins listed in Table 1, as well as a GLP-1 receptor agonists, insulin, Factor VII/VIIa, and functional analogs as described. Such agents may be prepared by recombinant technology and/or chemical coupling (e.g., conjugation).

A recombinantly-produced ELP fusion protein, in accordance with certain embodiments of the invention, includes the ELP component and the therapeutic component associated with one another by genetic fusion. For example, the fusion protein may be generated by translation of a polynucleotide encoding the therapeutic component cloned in-frame with the ELP component (or vice versa). Such an ELP fusion protein may contain one or more copies of the therapeutic component attached to the N-terminus and/or the C-terminus of the ELP component. In some embodiments, the therapeutic proteinacious component is attached to both the N- and C-terminus of the ELP component and the fusion protein may contain one or more equivalents of the therapeutic component on either or both ends of the ELP component.

In certain embodiments, the ELP component and the therapeutic components can be fused using a linker peptide of various lengths to provide greater physical separation and allow more spatial mobility between the fused portions, and thus maximize the accessibility of the therapeutic component, for instance, for binding to its cognate receptor. The linker peptide may consist of amino acids that are flexible or more rigid. For example, a flexible linker may include amino acids having relatively small side chains, and which may be hydrophilic. Without limitation, the flexible linker may contain a stretch of glycine and/or serine residues. More rigid linkers may contain, for example, more sterically hindering amino acid side chains, such as (without limitation) tyrosine or histidine. The linker may be less than about 50, 40, 30, 20, 10, or 5 amino acid residues. The linker can be covalently linked to and between an ELP component and a therapeutic component, for example, via recombinant fusion.

The linker or peptide spacer may be protease-cleavable or non-cleavable. By way of example, cleavable peptide spacers include, without limitation, a peptide sequence recognized by proteases (in vitro or in vivo) of varying type, such as Tev, thrombin, factor Xa, plasmin (blood proteases), metalloproteases, cathepsins (e.g., GFLG, etc.), and proteases found in other corporeal compartments. In some embodiments employing cleavable linkers, the fusion protein (“the therapeutic agent”) may be inactive, less active, or less potent as a fusion, which is then activated upon cleavage of the spacer in vivo. Alternatively, where the therapeutic agent is sufficiently active as a fusion, a non-cleavable spacer may be employed. The non-cleavable spacer may be of any suitable type, including, for example, non-cleavable spacer moieties having the formula [(Gly)n-Ser]m (SEQ ID NO.: 22) where n is from 1 to 4, inclusive, and m is from 1 to 4, inclusive. Alternatively, a short ELP sequence different than the backbone ELP could be employed instead of a linker or spacer, while accomplishing the necessary effect.

In still other embodiments, the therapeutic agent is a recombinant fusion having a therapeutic component flanked on each terminus by an ELP component. At least one of said ELP components may be attached via a cleavable spacer, such that the therapeutic component is inactive, but activated in vivo by proteolytic removal of a single ELP component. The resulting single ELP fusion being active, and having an enhanced half-life (or other property described herein) in vivo.

In other embodiments, the present invention provides chemical conjugates of the ELP component and the therapeutic component. The conjugates can be made by chemically coupling an ELP component to a therapeutic component by any number of methods well known in the art (See e.g. Nilsson et al., 2005, Ann Rev Biophys Bio Structure 34: 91-118). In some embodiments, the chemical conjugate can be formed by covalently linking the therapeutic component to the ELP component, directly or through a short or long linker moiety, through one or more functional groups on the therapeutic proteinacious component, e. g., amine, carboxyl, phenyl, thiol or hydroxyl groups, to form a covalent conjugate. Various conventional linkers can be used, e. g., diisocyanates, diisothiocyanates, carbodiimides, bis (hydroxysuccinimide) esters, maleimide-hydroxysuccinimide esters, glutaraldehyde and the like.

Non-peptide chemical spacers can additionally be of any suitable type, including for example, by functional linkers described in Bioconjugate Techniques, Greg T. Hermanson, published by Academic Press, Inc., 1995, and those specified in the Cross-Linking Reagents Technical Handbook, available from Pierce Biotechnology, Inc. (Rockford, Ill.), the disclosures of which are hereby incorporated by reference, in their respective entireties. Illustrative chemical spacers include homobifunctional linkers that can attach to amine groups of Lys, as well as heterobifunctional linkers that can attach to Cys at one terminus, and to Lys at the other terminus.

In certain embodiments, relatively small ELP components (e.g., ELP components of less than about 30 kDa, 25 kDa, 20 kDa, 15 kDa, or 10 kDa), that do not transition at room temperature (or human body temperature, e.g., Tt >37° C.), are chemically coupled or crosslinked. For example, two relatively small ELP components, having the same or different properties, may be chemically coupled. Such coupling, in some embodiments, may take place in vivo, by the addition of a single cysteine residue at or around the C-terminus of the ELP. Such ELP components may each be fused to one or more therapeutic components, so as to increase activity or avidity at the target.

Polynucleotides, Vectors, and Host Cells

In another aspect, the invention provides polynucleotides comprising a nucleotide sequence encoding the therapeutic agent of the invention. Such polynucleotides further comprise, in addition to sequences encoding the ELP and therapeutic components, one or more expression control elements. For example, the polynucleotide, may comprise one or more promoters or transcriptional enhancers, ribosomal binding sites, transcription termination signals, and polyadenylation signals, as expression control elements. The polynucleotide may be inserted within any suitable vector, which may be contained within any suitable host cell for expression.

A vector comprising the polynucleotide can be introduced into a cell for expression of the therapeutic agent. The vector can remain episomal or become chromosomally integrated, as long as the insert encoding the therapeutic agent can be transcribed. Vectors can be constructed by standard recombinant DNA technology. Vectors can be plasmids, phages, cosmids, phagemids, viruses, or any other types known in the art, which are used for replication and expression in prokaryotic or eukaryotic cells. It will be appreciated by one of skill in the art that a wide variety of components known in the art (such as expression control elements) may be included in such vectors, including a wide variety of transcription signals, such as promoters and other sequences that regulate the binding of RNA polymerase onto the promoter. Any promoter known to be effective in the cells in which the vector will be expressed can be used to initiate expression of the therapeutic agent. Suitable promoters may be inducible or constitutive. Examples of suitable promoters include the SV40 early promoter region, the promoter contained in the 3′ long terminal repeat of Rous sarcoma virus, the HSV-1 (herpes simplex virus-1) thymidine kinase promoter, the regulatory sequences of the metallothionein gene, etc., as well as the following animal transcriptional control regions, which exhibit tissue specificity and have been utilized in transgenic animals: elastase I gene control region which is active in pancreatic acinar cells; insulin gene control region which is active in pancreatic beta cells, immunoglobulin gene control region which is active in lymphoid cells, mouse mammary tumor virus control region which is active in testicular, breast, lymphoid and mast cells, albumin gene control region which is active in liver, alpha-fetoprotein gene control region which is active in liver, alpha 1-antitrypsin gene control region which is active in the liver, beta-globin gene control region which is active in erythroid cells, myelin basic protein gene control region which is active in oligodendrocyte cells in the brain, myosin light chain-2 gene control region which is active in skeletal muscle, and gonadotropin releasing hormone gene control region which is active in the hypothalamus.

Pharmaceutical Compositions

The present invention further provides pharmaceutical compositions comprising the therapeutic agents of the invention (as described above) together with a pharmaceutically acceptable carrier or excipient. Such pharmaceutical compositions may be employed in the methods of treatment as described above, for each of the therapeutic proteins, e.g., the therapeutic proteins listed in Table 1, GLP-1 receptor agonists, insulin, and Factor VII/VIIa embodiments.

The therapeutic agents of the invention may overcome certain deficiencies of peptide agents when administered (e.g., parenterally), including in some embodiments, the limitation that such peptides may be easily metabolized by plasma proteases or cleared from circulation by kidney filtration. Traditionally, the oral route of administration of peptide agents may also be problematic, because in addition to proteolysis in the stomach, the high acidity of the stomach destroys such peptide agents before they reach their intended target tissue. Peptides and peptide fragments produced by the action of gastric and pancreatic enzymes are cleaved by exo and endopeptidases in the intestinal brush border membrane to yield di- and tripeptides, and even if proteolysis by pancreatic enzymes is avoided, polypeptides are subject to degradation by brush border peptidases. Any of the peptide agents that survive passage through the stomach are further subjected to metabolism in the intestinal mucosa where a penetration barrier prevents entry into the cells. In certain embodiments, the therapeutic agents of the invention may overcome such deficiencies, and provide compositional forms having enhanced efficacy, bioavailability, therapeutic half-life, persistence, degradation assistance, etc. The therapeutic agents of the invention thus include oral and parenteral dose forms, as well as various other dose forms, by which peptide agents can be utilized in a highly effective manner. For example, in some embodiments, such agents may achieve high mucosal absorption, and the concomitant ability to use lower doses to elicit an optimum therapeutic effect.

The therapeutic agents of the present invention may be administered in smaller doses and/or less frequently than unfused or unconjugated counterparts. While one of skill in the art can determine the desirable dose in each case, a suitable dose of the therapeutic agent for achievement of therapeutic benefit, may, for example, be in a range of about 1 microgram (μg) to about 100 milligrams (mg) per kilogram body weight of the recipient per day, preferably in a range of about 10 μg to about 50 mg per kilogram body weight per day and most preferably in a range of about 10 μg to about 50 mg per kilogram body weight per day. The desired dose may be presented as one dose or two or more sub-doses administered at appropriate intervals throughout the day. These sub-doses can be administered in unit dosage forms, for example, containing from about 10 μg to about 1000 mg, preferably from about 50 μg to about 500 mg, and most preferably from about 50 μg to about 250 mg of active ingredient per unit dosage form. Alternatively, if the condition of the recipient so requires, the doses may be administered as a continuous infusion.

The mode of administration and dosage forms will of course affect the therapeutic amount of the peptide active therapeutic agent that is desirable and efficacious for a given treatment application. For example, orally administered dosages can be at least twice, e.g., 2-10 times, the dosage levels used in parenteral administration methods.

The therapeutic agents of the invention may be administered per se as well as in various forms including pharmaceutically acceptable esters, salts, and other physiologically functional derivatives thereof. The present invention also contemplates pharmaceutical formulations, both for veterinary and for human medical use, which include therapeutic agents of the invention. In such pharmaceutical and medicament formulations, the therapeutic agents can be used together with one or more pharmaceutically acceptable carrier(s) therefore and optionally any other therapeutic ingredients. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. The therapeutic agents are provided in an amount effective to achieve the desired pharmacological effect, as described above, and in a quantity appropriate to achieve the desired daily dose.

The formulations of the therapeutic agent include those suitable for parenteral as well as non-parenteral administration, and specific administration modalities include oral, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, intrathecal, intra-articular, intra-arterial, sub-arachnoid, bronchial, lymphatic, vaginal, and intra-uterine administration. Formulations suitable for oral and parenteral administration are preferred.

When the therapeutic agent is used in a formulation including a liquid solution, the formulation advantageously can be administered orally or parenterally. When the therapeutic agent is employed in a liquid suspension formulation or as a powder in a biocompatible carrier formulation, the formulation may be advantageously administered orally, rectally, or bronchially.

When the therapeutic agent is used directly in the form of a powdered solid, the active agent can be advantageously administered orally. Alternatively, it may be administered bronchially, via nebulization of the powder in a carrier gas, to form a gaseous dispersion of the powder which is inspired by the patient from a breathing circuit comprising a suitable nebulizer device.

The formulations comprising the therapeutic agent of the present invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation.

Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules; or a suspension in an aqueous liquor or a non-aqueous liquid, such as a syrup, an elixir, an emulsion, or a draught.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the therapeutic agent being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered peptide active therapeutic agent-ELP construct(s) with a suitable carrier may be made by molding in a suitable machine.

A syrup may be made by adding the peptide active therapeutic agent-ELP construct(s) to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.

Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the therapeutic agent, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents or other microparticulate systems which are designed to target the peptide active therapeutic agent to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.

Nasal spray formulations comprise purified aqueous solutions of the therapeutic agent with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucus membranes.

Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acid.

Topical formulations comprise the therapeutic agent dissolved or suspended in one or more media, such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.

In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.

The features and advantages of the present invention are more fully shown with respect to the following non-limiting examples.

EXAMPLES Example 1: Construction of Various ELP Component Constructs

Cloning steps were conducted in Escherichia coli strain XL1-Blue (rec A1, endA1, gyrA96, thi-1, hsdR17 (r_(k) ⁻, m_(k)+), supE44, relA1, lac[F′, proAB, lαcl^(q)ZΔM15, Tn10 (Tet^(r))] (Stratagene La Jolla, Calif.). pUC19 (NEB, Beverly, Mass.) was used as the cloning vector for the ELP construction (Meyer and Chilkoti, Nat. Biotechnol., 17(11):1112-5, 1999). Modified forms of pET15b and pET24d vectors (Novagen) were used to express ELP and ELP-fusion proteins in BL21 Star (DE3) strain (F⁻, ompT, hsdS_(B) (r_(B) ⁻ m_(B) ⁻), gal, dcm, rne131, (DE3)) (Invitrogen Carlsbed, Calif.) or BLR(DE3) (F⁻, ompT, hsdS_(B) (r_(B) ⁻ m_(B) ⁻), gal, dcm, Δ(srl-recA) 306::Tn10(TcR)(DE3)) (Novagen Madison, Wis.). Synthetic DNA oligos were purchased from Integrated DNA Technologies, Coralville, Iowa. All vector constructs were made using standard molecular biology protocols (e.g., Current Protocols in Molecular Biology, ed. Ausubel, et al., 1995).

Construction of ELP1 [V₅A₂G₃] Gene Series

The ELP1 [V₅A₂G₃] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is valine, alanine, and glycine at a relative ratio of 5:2:3.

The ELP1 [V₅A₂G₃] series monomer, ELP1 [V₅A₂G₃-10], was created by annealing four 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends (Meyer and Chilkoti, Nat. Biotechnol., 17(11):1112-5, 1999). The oligos were annealed in a 1 μM mixture of the four oligos in 50 μl IX ligase buffer (Invitrogen) to 95° C. in a heating block than the block was allowed to cool slowly to room temperature. The ELP1 [V₅A₂G₃-10]/EcoRI-HindIII DNA segment was ligated into a pUC19 vector digested with EcoRI and HindIII and CIAP dephosphorylated (Invitrogen) to form pUC19-ELP1 [V₅A₂G₃-10]. Building of the ELP1 [V₅A₂G₃] series library began by inserting ELP1 [V₅A₂G₃-10] PflMI/BglI fragment from pUC19-ELP1 [V₅A₂G₃-10] into pUC19-ELP1 [V₅A₂G₃-10] linearized with PflMI and dephosphorylated with CIAP to create pUC19-ELP1 [V₅A₂G₃-20]. pUC19-ELP1 [V₅A₂G₃-20] was then built up to pUC19-ELP1 [V₅A₂G₃-30] and pUC19-ELP1 [V₅A₂G₃-40] by ligating ELP1 [V₅A₂G₃-10] or ELP1 [V₅A₂G₃-20] PflMI/BglI fragments respectively into PflMI digested pUC 19-ELP1 [V₅A₂G₃-20]. This procedure was used to expand the ELP1 [V₅A₂G₃] series to create pUC19-ELP1 [V₅A₂G₃-60], pUC19-ELP1 [V₅A₂G₃-90] and pUC19-ELP1 [V₅A₂G₃-180] genes.

Construction of ELP1 [K₁V₂F₁] Gene Series

The ELP1 [K₁V₂F₁] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:2:1.

The ELP1 [K₁V₂F₁] series monomer, ELP1 [K₁V₂F₁-4], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends (Meyer and Chilkoti, 1999). The oligos were annealed in a 1 μM mixture of the four oligos in 50 μl 1× ligase buffer (Invitrogen) to 95° C. in a heating block then the block was allowed to cool slowly to room temperature. The ELP1 [K₁V₂F₁-4]/EcoRI-HindIII DNA segment was ligated into a pUC19 vector digested with EcoRI and HindIII and CIAP dephosphorylated (Invitrogen) to form pUC19-ELP1 [K₁V₂F₁-4]. Building of the ELP1 [K₁V₂F₁] series library began by inserting ELP1 [K₁V₂F₁-4] PflMI/Bgl1 fragment from pUC19-ELP1 [K₁V₂F₁-4] into pUC19-ELP1 [K₁V₂F₁-4] linearized with PflM1 and dephosphorylated with CIAP to create pUC19-ELP1 [K₁V₂F₁-8]. Using the same procedure the ELP1 [K₁V₂F₁] series was doubled at each ligation to form pUC19-ELP1 [K₁V₂F₁-16], pUC19-ELP1 [K₁V₂F₁-32], pUC19-ELP1 [K₁V₂F₁-64] and pUC19-ELP1 [K₁V₂F₁-128].

Construction of ELP1 [K₁V₇F₁] Gene Series

The ELP1 [K₁V₇F₁] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:7:1.

The ELP1 [K₁V₇F₁] series monomer, ELP1 [K₁V₇F₁-9], was created by annealing four 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with PflMI and HindIII compatible ends. The ELP1 [K₁V₇F₁-9] DNA segment was than ligated into PflM1/HindIII dephosphorylated PUC19-ELP1 [V₅A₂G₃-180] vector thereby substituting ELP1 [V₅A₂G₃-180] for ELP1 [K₁V₇F₁-9] to create the pUC19-ELP1 [K₁V₇F₁-9] monomer. The ELP1 [K₁V₇F₁] series was expanded in the same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP1 [K₁V₇F₁-18], PUC19-ELP1 [K₁V₇F₁-36], pUC19-ELP1 [K₁V₇F₁-72] and pUC19-ELP1 [K₁V₇F₁-144].

Construction of ELP1 M Gene Series

The ELP1 [V] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is exclusively valine.

The ELP1 [V] series monomer, ELP1 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP1 [V-5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP1 [V-5] monomer. The ELP1 [V] series was created in the same manner as the ELP1 [V₅A₂G₃] series, ultimately expanding pUC19-ELP1 [V-5] to pUC19-ELP1 [V-60] and pUC19-ELP1 [V-120].

Construction of ELP2 Gene Series

The ELP2 series designate polypeptides containing multiple repeating units of the pentapeptide AVGVP.

The ELP2 series monomer, ELP2 [5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP2 [5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP2[5] monomer. The ELP2 series was expanded in the same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP2[10], pUC19-ELP2 [30], pUC 19-ELP2 [60] and pUC 19-ELP2 [120].

Construction of ELP3 M Gene Series

The ELP3 [V] series designate polypeptides containing multiple repeating units of the pentapeptide IPGXG (SEQ ID NO: 5), where X is exclusively valine.

The ELP3 [V] series monomer, ELP3 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with PfLM1 amino terminal and GGC carboxyl terminal compatible ends due to the lack of a convenient carboxyl terminal restriction site but still enable seamless addition of the monomer. The ELP3 [V-5] DNA segment was then ligated into PflM1/BglI dephosphorylated pUC19-ELP4[V-5], thereby substituting ELP4 [V-5] for ELP3 [V-5] to create the pUC19-ELP3 [V-5] monomer. The ELP3 [V] series was expanded by ligating the annealed ELP3 oligos into pUC19-ELP3[V-5] digested with PflMI. Each ligation expands the ELP3 [V] series by 5 to create ELP3 [V-10], ELP3 [V-15], etc.

Construction of the ELP4 M Gene Series

The ELP4 [V] series designate polypeptides containing multiple repeating units of the pentapeptide LPGXG (SEQ ID NO: 7), where X is exclusively valine.

The ELP4 [V] series monomer, ELP4 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP4 [V-5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP4[V-5] monomer. The ELP4 [V] series was expanded in the same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP4[V-10], pUC19-ELP4[V-30], pUC19-ELP4[V-60] and pUC19-ELP4[V-120].

The ELP genes were also inserted into other vectors such as pET15b-SD0, pET15b-SD3, pET15b-SD5, pET15b-SD6, and pET24d-SD21. The pET vector series are available from Novagen, San Diego, Calif.

The pET15b-SD0 vector was formed by modifying the pET15b vector using SD0 double-stranded DNA segment containing the multicloning restriction site (SacI-NdeI-NcoI-XhoI-SnaBI-BamHI). The SD0 double-stranded DNA segment had XbaI and BamHI compatible ends and was ligated into XbaI/BamHI linearized and 5-dephosphorylated pET15b to form the pet15b-SD0 vector.

The pET15b-SD3 vector was formed by modifying the pET15b-SD0 vector using SD3 double-stranded DNA segment containing a SfiI restriction site upstream of a hinge region-thrombin cleavage site followed by the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD3 double-stranded DNA segment had SacI and NdeI compatible ends and was ligated into SacI/NdeI linearized and 5-dephosphorylated pET15b-SD0 to form the pET15b-SD3 vector.

The pET15b-SD5 vector was formed by modifying the pET15b-SD3 vector using the SD5 double-stranded DNA segment containing a SfiI restriction site upstream of a thrombin cleavage site followed by a hinge and the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD5 double-stranded DNA segment had SfiI and NdeI compatible ends and was ligated into SfiI/NdeI linearized and 5-dephosphorylated pET15b-SD3 to form the pET15b-SD5 vector.

The pET15b-SD6 vector was formed by modifying the pET15b-SD3 vector using the SD6 double-stranded DNA segment containing a SfiI restriction site upstream of a linker region-TEV cleavage site followed by the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHÏ). The SD6 double-stranded DNA segment had SfiI and NheI compatible ends and was ligated into SfiI/NdeI linearized and 5-dephosphorylated pET15b-SD3 to form the pET15b-SD6 vector.

The pET24d-SD21 vector was formed by modifying the pET24d vector using the SD21 double-stranded DNA segment with NcoI and NheI compatible ends. The SD21 double-stranded DNA segment was ligated into NcoI/NheI linearized and 5′ dephosphorylated pET24d to create the pET24d-SD21 vector, which contained a new multi-cloning site NcoI-SfiI-NheI-BamHI-EcoRI-SacI-San-HindIII-NotI-XhoI with two stop codons directly after the SfiI site for insertion and expression of ELP with the minimum number of extra amino acids.

The pUC19-ELP1 [V₅A₂G₃-60], pUC19-ELP1 [V₅A₂G₃-90], and pUC19-ELP1 [V₅A₂G₃-180] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET15b-SD3 expression vector as described hereinabove to create pET15b-SD3-ELP1 [V₅A₂G₃-60], pET15b-SD5-ELP1 [V₅A₂G₃-90] and pET15b-SD5-ELP1 [V₅A₂G₃-180], respectively.

The pUC19-ELP1 [V₅A₂G₃-90], pUC19-ELP1 [V₅A₂G₃-180], pUC19-ELP1 [V-60] and pUC19-ELP1 [V-120] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET15b-SD5 expression vector as described hereinabove to create pET15b-SD5-ELP1 [V₅A₂G₃-90], pET15b-SD5-ELP1 [V₅A₂G₃-180], pET15b-SD5-ELP1 [V-60] and pET15b-SD5-ELP1 [V-120], respectively.

The pUC19-ELP1 [V₅A₂G₃-90] plasmid produced in XL1-Blue was digested with PflMI and BglI, and the ELP-containing fragment was ligated into the SfiI site of the pET15b-SD6 expression vector as described hereinabove to create pET15b-SD6-ELP1 [V₅A₂G₃-90].

The pUC19-ELP1 [K₁V₂F₁-64], and pUC19-ELP1 [K₁V₂F₁-128] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP1 [K₁V₂F₁-64] and pET24d-SD21-ELP1 [K₁V₂F₁-128], respectively.

The pUC19-ELP1 [K₁V₇F₁-72] and pUC19-ELP1 [K₁V₇F₁-144] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP1 [K₁V₇F₁-72], pET24d-SD21-ELP1 [K₁V₇F₁-144], respectively.

The pUC19-ELP2[60] and pUC19-ELP2[120] plasmids produced in XL1-Blue were digested with NcoI and HindIII, and the ELP-containing fragments were ligated into the NcoI and HindIII sites of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP2[60], pET24d-SD21-ELP2[120], respectively.

The pUC19-ELP4[V-60] and pUC19-ELP4[V-120] plasmids produced in XL1-Blue were digested with NcoI and HindIII, and the ELP-containing fragments were ligated into the NcoI and HindIII sites of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP4[V-60], pET24d-SD21-ELP4[V-120], respectively.

Example 2: Isolation and Purification of Fusion Proteins Containing Insulin a Peptide (Insa)

ELP-InsA fusion proteins included the following:

Insulin A peptide and ELP1 [V-60] polypeptide with an enterokinase protease cleavage site therebetween.

Insulin A peptide and ELP1 [V₅A₂G₃-90] polypeptide with an enterokinase protease cleavage site therebetween.

Insulin A peptide and ELP1 [V-120] polypeptide with an enterokinase protease cleavage site therebetween.

Insulin A peptide and ELP1 [V₅A₂G₃-180] polypeptide with an enterokinase protease cleavage site therebetween.

A single colony of E. coli strain BLR (DE3) (Novagen) containing the respective ELP-InsA fusion protein was inoculated into 5 ml CircleGrow (Q-BIOgene, San Diego, Calif.) supplemented with 100 μg/ml ampicillin (Sigma) and grown at 37° C. with shaking at 250 rpm for 5 hours. The 5 ml culture was then inoculated into a 500 ml culture and allowed to grow at 25° C. for 16 hours before inducing with 1 mM IPTG for 4 hours at 25° C. The culture was harvested and suspended in 40 ml 20 mM Tris-HCl pH 7.4, 50 mM NaCl, 1 mM DTT and 1 Complete EDTA free Protease inhibitor pellet (Roche, Indianapolis, Ind.). Cells were lysed by ultrasonic disruption on ice for 3 minutes, which consisted of 10 seconds bursts at 35% power separated by 30 second cooling down intervals. Cell debris was removed by centrifugation at 20,000 g, 4° C. for 30 minutes.

Inverse phase transition was induced by adding NaCl to the cell lysate at room temperature to achieve a final concentration of 1.0 M therein, followed by centrifugation at 20,000 g for 15 minutes at room temperature. The resulting pellet contained the respective ELP-InsA fusion protein and non-specifically NaCl precipitated proteins.

The pellet was re-suspended in 40 ml ice-cold ml 20 mM Tris-HCl pH 7.4, 50 mM NaCl, 1 mM DTT and re-centrifuged at 20,000 g, 4° C. for 15 minutes to remove the non-specifically NaCl precipitated proteins. The inverse transition cycle was repeated two additional times to increase the purity of the respective ELP-InsA fusion protein and reduce the final volume to 0.5 ml.

Example 3: Half-Life of ELP1

The pharmacokinetics of ELP1 were determined by intravenously administering [¹⁴C]ELP1 to nude mice (Balb/c nu/nu) bearing a leg/flank FaDu xenograft and collecting blood samples at various time intervals after administration. The blood pharmacokinetics exhibited a characteristic distribution and elimination response for large macromolecules, which was well described by a bi-exponential process.

The plasma concentration time-course curve was fit to the analytical solution of a two-compartment model to approximate both an elimination and distribution response. Certain pharmakinetic parameters are shown in Table 1 below. The distribution volume of the ELP (1.338 μl) was nearly identical to the hypothetical plasma volume of 1.363 μl (Barbee, R. W., et al., Am. J. Physio. 263(3) (1992) R728-R733), indicating that the ELP did not rapidly distribute or bind to specific organs and tissues directly after administration. The AUC is a measure of the cumulative exposure to ELP in the central compartment or the blood plasma. The body clearance is defined as the rate of ELP elimination in the body relative to its plasma concentration and is the summation of clearance through all organs including the kidney, liver and others.

TABLE 1 Pharmacokinetic parameters calculated for [¹⁴C]ELP1 k₁ k₂ k_(e) V_(d) AUC Cl_(B) (hr⁻¹) (hr⁻¹) (hr⁻¹) (μL) (mg ELP hr/ml) (μL/hr) ELP1-150 3.54 1.99 0.24 1,338 7.1 317

The mass transfer rate constants are from a standard two-compartment model (k₁; from central to peripheral compartment; k₂, from peripheral to central compartment; and k_(e), elimination from central compartment). The distribution volume (V_(d)), central compartment concentration time-course area under the curve (AUC) and body clearance (Cl_(B)) are displayed. Data are shown as the mean values (n=5, except V_(d) and initial plasma concentration (C_(O)) was calculated from a similar cohort with n=3).

Example 4: Biodistribution of ELPs in Nude Mice

¹⁴C Labeled ELP1-150 and/or ¹⁴C Labeled ELP2-160

¹⁴C labeled ELP1-150 and/or ¹⁴C labeled ELP2-160 were administered to nude mice with a FaDu tumor (mean+/−SD, n=6). The tumor was heated post administration of the ELP in a water bath at 41.5° C. The distribution was highest to the organs with the highest blood content: liver, kidneys, spleen, and lungs.

¹⁴C Labeled ELP2-[V₁A₈G₇-160]

¹⁴C labeled ELP2-[V₁A₈G₇-160] (T_(t)>60° C.) was administered to nude mice for a plasma concentration of 15 μM. ELP concentrations were determined following 1 hour of heating (41° C.) of an implanted FaDu tumor, located in the right hind leg of the nude mouse. Data are shown as the mean, plus the 95% confidence interval. N=6.

ELP concentration was measured 1.5 hours following systemic administration of ¹⁴C labeled ELP2-[V₁A₈G₇-160]. The highest distribution is seen in organs with the highest blood content: liver, kidneys, spleen, and lungs.

Example 5: Exendin-4 ELP Fusion

The DNA sequence for Exendin-4 (Ex-4) (SEQ ID NO: 14) was reverse translated from the amino acid sequence using codons optimized for E. coli expression. The DNA sequence encoding Exendin-4 was constructed by annealing together synthetic oligonucleotides with overhanging 5′ and 3′ ends compatible with the restriction sites NdeI and XhoI in the plasmid pET24d-ELP1-90 (FIG. 1 ). This plasmid was digested with the restriction enzymes NdeI and XhoI and the annealed DNA sequence was ligated into the cut vector. Insertion was confirmed by restriction digest and DNA sequencing. The resulting plasmid was designated as pET24d-Ex-4 ELP1-90 (FIG. 2A), and the sequence of the resulting Exendin-4-ELP fusion shown in FIG. 2B. Primers for construction of the fusion are also indicated.

pET24d-Ex-4 ELP1-90 was used to transform the E. coli strain BRL (Invitrogen) and selected transformants were grown in media 3 (1.2% Tryptone Peptone, 2.4% yeast extract, 5 g/L casamino acids, 2% glycerol, 2.313 g Potassium phosphate dibasic/L, 12.541 g Potassium phosphate monobasic/L) in shake flasks. Production proceeded by autoinduction by inoculating 1 OD cells into 1L of media 3 and allowing growth to proceed for 17 hr at 37° C. without addition of inducer. The product was recovered by collection of the cell pellet, sonicated to disrupt the cells and recovered by thermal and/or salt induced transition modulated by the ELP moiety (Improved Non-chromatographic Purification of a Recombinant Protein by Cationic Elastin-like Polypeptides, Dong Woo Lim, Kimberly Trabbic-Carison, J. Andrew MacKay, and Ashutosh Chilkoti. Biomacromolecules 2007, 8, 1417-1424).

This example is with the ELP designated 1-90. This is based on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2 in a 10 unit repeat, repeated 8× with a final (C-terminal) 10-unit repeat where X is a V, G, A and W in the ratio 4:3:2:1.

[(VPGXG)10]₉ where the X residue in the ten sequential iterations of the repeat unit (numerical subscript) can be described as [(V_(1, 4, 5, 6, 10)G_(2, 7, 9)A_(3, 8))₈ (V_(1, 4, 5, 6)G_(2, 7, 9)A_(3, 8) W₁₀)].

The ELP may be any combination of VPGXG (SEQ ID NO: 3) units where X is any of the 20 natural amino, acids, except proline, in any combination of repeat units of any length. In addition, the amino acid may be an unnatural amino acid for which the host strain has been engineered to accept an engineered tRNA for incorporation at specific codon (Wang L, Brock A, Herberich B, Schultz PG. Expanding the genetic code of Escherichia coli. [2001] Science 292, 498-500).

This construct was produced in the cytosol with an N-terminal methionine, which is normally removed by methionine aminopeptidase. Complete and accurate processing of the methionine, however, cannot be assumed; this enzyme may also remove the N-terminal histidine of the Exendin-4 moiety. This could result in a mixture of, unprocessed, processed and incorrectly processed products. Consequently, further constructs were developed to generate products with correctly processed N-termini.

Primers were designed to add a Tev protease (Tobacco Etch Virus cysteine protease) cleavage site between the N-terminal methionine and the histidine at the N-terminus of Exendin-4. This allows for removal of the methionine and the Tev recognition sequence to give the mature N-terminus of Exendin-4 (histidine). This can be done post-production or the Tev protease can be co-expressed to cleave the recognition sequence during production, for instance, as an intein (Ge, X., Yang, D. S. C., Trabbic-Carison, K., Kim, B., Chilkoti, A. and Filipe, C. D. M. Self-Cleavable Stimulus Responsive Taos for Protein Purification without Chromatography. J. Am. Chem. Soc. 127, 11228-11229, 2005). The Tev Exendin-4 sequence is shown in FIG. 3A. FIG. 3B shows additional sequences added, labeled as “Linker Tev,” provide a better target for the Tev protease.

An alternative route to obtaining a correctly processed N-terminus for Ex-4 is to use a leader or signal sequence that directs the product to the periplasm and which is cleaved by a signal peptidase in the process. In this instance, a signal sequence, DsbA, that directs the transcript to the signal recognition particle for direct secretion of the polypeptide into the periplasm is given. (See FIG. 4A). The plasmid pET24d-DsbA-Ex-4 ELP1-90 is shown in FIG. 4B.

While this example illustrates the preparation of therapeutic agents with Exendin-4 sequences, such sequences can be replaced with GLP-1, insulin, Factor VII/VIIa, or other therapeutic protein listed in Table 1, generated in exactly or a similar manner as detailed for Exendin-4.

Example 6: GLP1-ELP Fusion Protein

The ELP plasmid constructs were used to prepare two GLP1-ELP fusion proteins, GLP1(A8G,7-37)ELP1-90 and GLP1(A8G,7-37)ELP1-120. The plasmid constructs, fusion-encoding nucleotide sequence, as well as the amino acid sequence of the resulting fusion proteins are shown in FIGS. 5 and 6 .

Both constructs contain an N-terminal Tev protease site to allow processing to the mature form where His⁷ of GLP1 is at the N-terminus. The processed fusion proteins have calculated molecular weights of about 39,536 and about 50,828, respectively.

Example 7: FVII ELP Fusion Protein

The coagulation factor VII (FVII) gene was modified by PCR from a cDNA clone (Oragene) to add restriction sites at the 5′ and 3′ ends for cloning into the ELP-containing vector. At the 5′ end an NheI site was added and at the 3′ end a NotI site was added. The DNA and amino acid sequences of the Factor VII gene are shown in the accompanying Sequence Listing as SEQ ID NOS: 34 and 33, respectively. The DNA sequences of the 5′ and 3′ primers used to PCR amplify the factor VII (FVII) gene were:

P13: (SEQ ID NO.: 49) CTAGCTAGCATGGTCTCCCAGGCCCTC P14: (SEQ ID NO.: 50) TATTCTTGCGGCCGCGGGAAATGGGGCTCGCAG

The resulting PCR fragment was digested with the restriction enzymes NheI and NotI and ligated into the plasmid pcDNA3.1+ ELP1-90 previously digested with the restriction enzymes NheI and NotI (FIG. 7A).

The resulting plasmid, pcDNA3.1+ FVII-ELP1-90, was transiently transfected into HEK293 cells and culture media harvested. The ELP fusion was purified by phase transition (FIGS. 9 and 10 ).

The nucleotide and amino acid sequences of the FactorVII-ELP fusion is shown in FIG. 7B. As shown, the FactorVII-ELP fusion protein contains a Tev protease linker between the FactorVII component and the ELP component. This linker is optional.

Example 8: Insulin ELP Fusion Protein

The cDNA for the human insulin gene is modified at the 5′ and 3′ ends for insertion in to pET24d-ELP1-90. The 5′ primer adds an N-terminal methionine for bacterial expression and an NdeI restriction enzyme site. The 3′ primer adds an XhoI restriction enzyme site. The PCR product and the plasmid are both digested with the restriction enzymes NdeI and XhoI and ligated together. The sequence of the insulin (Chains B, C, and A fused to ELP1 is shown in FIG. 8A.

Correct insertion is determined by restriction digest and DNA sequencing. The resulting plasmid, designated pET24d Insulin-ELP1-90, is shown in FIG. 8B.

The native insulin form is generated after recovery from E. coli by treatment with trypsin and carboxypeptidase B to remove the C-peptide chain.

For correct processing of the N-terminus of the B-chain similar modifications to those made for the Exendin-4 fusion (protease cleavage site, signal sequence) can be implemented (see Example 4). Alternatively, the first two residues can be Met-Arg, which can also be removed by trypsin digestion in production of the final material (R. M. Belagaje, S. G. Reams, S. C. Ly and W. F. Prouty, Increased production of low molecular weight recombinant proteins in Escherichia coli. Protein Sci. 6, 1953-1962, 1997).

Additional constructs would place the insulin cDNA at the 3′ end of the ELP for a C-terminal fusion, add linkers between the Insulin and ELP sequences, and/or use modified forms of insulin which have no C-peptide (single chain insulins as described) removing the need for additional processing.

Example 9: Synthesis of the ELP Gene for Conjugation

A gene encoding a 50 amino acid sequence was constructed from chemically-synthesized oligonucleotides using standard molecular biology protocols. The 50 amino acid sequence contained 10 repeats of the pentapeptide VPGXG (SEQ ID NO: 3), where the guest residues (V, G, and A in a 5:3:2 molar ratio) were selected to provide a Tt of 40° C. The gene was oligomerized end-to-end by standard molecular biology techniques, to produce an oligomeric ELP gene. Additionally a single 50 amino acid sequence was constructed containing the 10 repeat pentapeptide VPGXG (SEQ ID NO: 3) polypeptide where the guest residues were V, G, A and C in a 4:3:2:1 molar ratio. This sequence could be added at any cycle of the oligomerization process to introduce a single cysteine residue into the final construct at a chosen point along the length of the construct.

The example given here is with the ELP designated 1-90. This is based on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2 in a 10-unit repeat, repeated 8× with a final (C-terminal) 10-unit repeat where X is a V, G, A and C in the ratio 4:3:2:1, i.e., [(VPGXG)10]9 (SEQ ID NO.: 3).

Alternatively, the residue could be one of either arginine, lysine, aspartic acid or glutamic acid. The purpose of these amino acids is to provide a reactive side chain for the chemical conjugation of, for example, insulin. In this particular case the use of an ELP would be to extend the circulating half-life of the therapeutic protein (e.g., insulin) to provide prolonged basal glucose control. Conjugated to an ELP that transitions at body temperature, the insulin would form a precipitated depot at the site of injection in a similar manner to Lantus® (Sanofi Aventis) but without the requirement for formulation in acidic (pH 4.0) conditions with m-cresol for a more tolerable injection.

Example 10: Potency and Half-Life of Factor VII-ELP

FIG. 11 shows the activation of Factor X by FactorVIIa-ELP1-90, and by Factor VIIa as a comparison. Factor VII-ELP was produced in HEK cells. Factor VIIa was derived from human plasma. As shown, FactorVIIa-ELP retains full activity.

When administered to rats by i.v., Factor VII-ELP demonstrated a half-life of about 690 minutes. In contrast, Factor VII demonstrated a half-life of 45-60 minutes. Half-life in this example was measured by sandwich ELISA for FactorVII. FIG. 12 .

Also in contrast, the reported half-life for NovoSeven™ is 45 minutes, the reported half-life for FactorVIIa-albumin fusion is 263 minutes, and the reported half-life for Factor VIIa-PEG is 300 minutes in mice and 600 minutes in dog.

Example 11: GLP-1 (or Exendin-4) In Vitro Bioassay

Activation of the GLP-1 receptor (GLP1R) results in production of cAMP secondary messenger within the cell. Therefore, GLP-1 or Exendin-4 analogs and corresponding therapeutic agents may be tested by their ability to activate GLP1R on the cell surface and produce cAMP.

For this bioassay CHO cells transfected with cDNA coding for GLP1R are used. These cells respond to stimulation by GLP-1 and produce high levels of cAMP. Log phase growing cells are plated and increasing concentrations of test compounds (e.g., therapeutic agent of the invention, or GLP-1 or exendin-4 functional analog) are added to the cells. After an appropriate incubation period (usually 15-60 min) in physiological buffer at 37° C. the cAMP produced is measured using a CatchPoint cAMP assay kit from Molecular Devices (Sunnyvale, Calif.). The EC₅₀ of each test compound as compared to GLP-1 peptide or Exendin-4 peptide (or as compared to an unfused or unconjugated counterpart of a therapeutic agent of the invention) is indicative of the changes in activity due to a specific modifications introduced into the peptide, or due to particular chemical or recombinant coupling to an ELP component.

As shown in FIG. 13 , both GLP1-ELP (PB0868) and Exendin-4-ELP (PB 0859) maintain high activity in vitro, shown in comparison to Exendin alone. It is of note that the specific activity of Albugon® and Liraglutide® run 50-100 fold less than the exendin peptide.

Example 12: GLP-1 (or Exendin-4) In Vivo Bioassay

The activity of GLP-1 or Exendin analogues or corresponding therapeutic agents may be tested in animals. For this assay, normal or diabetic animals may be used. Diabetic animals with blood glucose concentration 300-500 mg/dl are injected with different doses of GLP-1 or Exendin analogues or corresponding therapeutic agent, and changes in blood glucose monitored with a glucometer. The drop in glucose at different times points post administration is compared to that resulting with standard amounts of GLP-1 or Exendin-4 peptide, or compared to an unfused or unconjugated counterpart of a therapeutic agent of the invention. Alternatively, the blood glucose excursion in normal or diabetic animals during specific time period after administration of exogenous glucose is compared to GLP-1 or Exendin-4 (or to unfused or unconjugated counterparts of therapeutic agents). In this way the activity of the analogues and fusion proteins can be compared to the natural peptides.

FIG. 14 shows the pharmacokinetics of GLP1-ELP1-120 in rats administered both by i.v. and subcutaneously. Three rats were used for each time point. The dose was ˜10 mg/kg. The T_(1/2) when administered by i.v. was about 12.9 hours. The T_(1/2) when administered subcutaneously was about 8.6 hours.

FIG. 15 shows the pharmacokinetics of GLP1-ELP1-120 in rabbits administered both by i.v. and subcutaneously. Three rabbits were used for each time point. The dose was ˜1 mg/kg. The T_(1/2) when administered by i.v. was about 20 hours. The T_(1/2) when administered subcutaneously was about 24 hours.

FIG. 16 shows the sustained glycemic control in diabetic mice with GLP1-ELP1-90.

All reference cited herein are hereby incorporated by reference in their entireties. While the invention has been has been described herein in reference to specific aspects, features and illustrative embodiments of the invention, it will be appreciated that the utility of the invention is not thus limited, but rather extends to and encompasses numerous other variations, modifications and alternative embodiments, as will suggest themselves to those of ordinary skill in the field of the present invention, based on the disclosure herein 

What is claimed is:
 1. A therapeutic agent comprising an elastin-like peptide (ELP) component and a therapeutic component, the therapeutic component having an extended circulatory half-life and/or a lower therapeutically effective dose when compared to the therapeutic component alone.
 2. The therapeutic agent of claim 1, wherein the therapeutic component is a therapeutic protein listed in Table 1 or a functional portion or functional analog thereof.
 3. The therapeutic agent of claim 2, wherein an ELP component is covalently bonded to the therapeutic protein at an N- and/or C-terminus thereof.
 4. The therapeutic agent of any one of claims 1-3, wherein a therapeutic component is covalently bonded to the ELP component at the N-terminus of the ELP component, and a second therapeutic component is covalently bonded to the ELP component at the C-terminus of the ELP component.
 5. The therapeutic agent of any one of claims 1-4, wherein a therapeutic component is covalently bonded to the ELP component at an N- and/or C-terminus thereof.
 6. The therapeutic agent of any one of claims 1-5, wherein a first ELP component is covalently bonded to the therapeutic component at the N-terminus of the therapeutic component, and a second ELP component is covalently bonded to the therapeutic component at the C-terminus of the therapeutic component.
 7. The therapeutic agent of any one of claims 1-6, further comprising a spacer moiety between the ELP component and the therapeutic component.
 8. The therapeutic agent of claim 7, wherein the spacer moiety comprises one or more of a protease-resistant moiety, a non-peptide chemical moiety, and a protease cleavage site.
 9. The therapeutic agent of claim 8, wherein the protease cleavage site is a thrombin cleavage site, a factor Xa cleavage site, a metalloprotease cleavage site, an enterokinase cleavage site, a Tev cleavage site, and a cathepsin cleavage site.
 10. The therapeutic agent of claim 9, wherein the spacer moiety comprises a non-cleavable moiety having the formula [(Gly)_(n)-Ser]_(m) (SEQ ID NO: 22) where n is from 1 to 4, inclusive, and m is from 1 to 4, inclusive.
 11. The therapeutic agent of any one of claims 1-10, wherein the ELP comprises at least one repeating unit selected from SEQ ID NOS: 1-12.
 12. The therapeutic agent of claim 11, wherein said repeating unit is VPGXG (SEQ ID NO: 3).
 13. The therapeutic agent of claim 12, wherein X is any natural or non-natural amino acid residue, and wherein X varies among at least two units.
 14. The therapeutic agent of claim 13, wherein each X is independently selected from alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine residues.
 15. The therapeutic agent of any one of claims 1-14, wherein the therapeutic agent has a molecular weight of less than about 50 kDa.
 16. The therapeutic agent of any one of claims 1-15, wherein the ELP component has a Tt greater than 37° C.
 17. The therapeutic agent of any one of claims 1-16, wherein the therapeutic agent is a genetically encoded fusion protein.
 18. A polynucleotide comprising a nucleotide sequence encoding the therapeutic agent of claim
 17. 19. The polynucleotide of claim 18, further comprising an expression control element operably linked to said nucleotide sequence.
 20. The polynucleotide of claim 19, wherein said expression control element comprises a promoter.
 21. A vector comprising the polynucleotide of any one of claims 18-20.
 22. An isolated host cell containing the vector of claim 21 or the polynucleotide of any one of claims 18-20.
 23. A pharmaceutical composition comprising the therapeutic agent of any one of claims 1-18, and a pharmaceutically acceptable carrier and/or excipient.
 24. A method of treating or preventing a disease, disorder, or condition in a subject, comprising administering an effective amount of the therapeutic agent of any one of claims 1-17 or the pharmaceutical composition of claim 23 to a subject in need thereof.
 25. The method of claim 24, wherein the subject has an indication listed in Table
 1. 26. A therapeutic agent comprising an elastin-like peptide (ELP) component and a glucagon-like peptide (GLP)-1 receptor agonist.
 27. The therapeutic agent of claim 26, wherein the GLP-1 receptor agonist is GLP-1 or functional analog thereof.
 28. The therapeutic agent of claim 26, wherein the GLP-1 receptor agonist is an exendin-4 or functional analog thereof.
 29. The therapeutic agent of any one of claims 26-28, wherein the ELP component is covalently bonded to the GLP-1 receptor agonist at an N- and/or C-terminus thereof.
 30. The therapeutic agent of any one of claims 26-29, wherein a first GLP-1 receptor agonist is covalently bonded to the ELP component at the N-terminus of the ELP component, and a second GLP-1 receptor agonist is covalently bonded to the ELP component at the C-terminus of the ELP component.
 31. The therapeutic agent of any one of claims 26-30, wherein the GLP-1 receptor agonist is covalently bonded to the ELP component at an N- and/or C-terminus thereof.
 32. The therapeutic agent of any one of claims 26-31, wherein a first ELP component is covalently bonded to the GLP-1 receptor agonist at the N-terminus of the GLP-1 receptor agonist, and a second ELP component is covalently bonded to the GLP-1 receptor agonist at the C-terminus of the GLP-1 receptor agonist.
 33. The therapeutic agent of any one of claims 26-32, further comprising a spacer moiety between the ELP component and GLP-receptor agonist.
 34. The therapeutic agent of claim 33, wherein the spacer moiety comprises one or more of a protease-resistant moiety, a non-peptide chemical moiety, and a protease cleavage site.
 35. The therapeutic agent of claim 34, wherein the protease cleavage site is a thrombin cleavage site, a factor Xa cleavage site, a metalloprotease cleavage site, an enterokinase cleavage site, a Tev cleavage site, and a cathepsin cleavage site.
 36. The therapeutic agent of claim 34, wherein the spacer moiety comprises a non-cleavable moiety having the formula [(Gly)_(n)-Ser]_(m) (SEQ ID NO.: 22) where n is from 1 to 4, inclusive, and m is from 1 to 4, inclusive.
 37. The therapeutic agent of any one of claims 26-36, wherein the ELP comprises at least one repeating unit selected from SEQ ID NOS: 1-12.
 38. The therapeutic agent of claim 37, wherein said repeating unit is VPGXG (SEQ ID NO: 3).
 39. The therapeutic agent of claim 38, wherein X is any natural or non-natural amino acid residue, and wherein X varies among at least two units.
 40. The therapeutic agent of claim 38, wherein each X is independently selected from alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine residues.
 41. The therapeutic agent of any one of claims 26-40, wherein the therapeutic agent has a molecular weight of less than about 50 kDa.
 42. The therapeutic agent of any one of claims 26-40, wherein the ELP component has a Tt greater than 37° C.
 43. The therapeutic agent of any one of claims 26-42, wherein the therapeutic agent is a genetically encoded fusion protein.
 44. A polynucleotide comprising a nucleotide sequence encoding the therapeutic agent of claim
 43. 45. The polynucleotide of claim 44, further comprising an expression control element operably linked to said nucleotide sequence.
 46. The polynucleotide of claim 45, wherein said expression control element comprises a promoter.
 47. A vector comprising the polynucleotide of any one of claims 44-46.
 48. An isolated host cell containing the vector of claim 47 or the polynucleotide of any one of claims 44-46.
 49. A pharmaceutical composition comprising the therapeutic agent of any one of claims 26-43, and a pharmaceutically acceptable carrier and/or excipient.
 50. A method of treating or preventing a biological condition, disorder, or disease in a subject, comprising administering an effective amount of the therapeutic agent of any one of claims 26-43 or the pharmaceutical composition of claim 49 to a subject in need thereof.
 51. The method of claim 50, wherein the subject has diabetes.
 52. A therapeutic agent comprising an elastin-like peptide (ELP) component and an insulin or functional analog thereof.
 53. The therapeutic agent of claim 52, wherein the ELP component is covalently bonded to the insulin or functional analog at an N- and/or C-terminus thereof.
 54. The therapeutic agent of claim 52 or 53, wherein a first insulin or functional analog is covalently bonded to the ELP component at the N-terminus of the ELP component, and a second insulin or functional analog is covalently bonded to the ELP component at the C-terminus of the ELP component.
 55. The therapeutic agent of claim 52, wherein the insulin or functional analog is covalently bonded to the ELP component at an N- and/or C-terminus thereof.
 56. The therapeutic agent of claim 52 or 53, wherein a first ELP component is covalently bonded to the insulin or functional analog at an N-terminus thereof, and a second ELP component is covalently bonded to the insulin or functional analog at a C-terminus thereof.
 57. The therapeutic agent of any one of claims 52-56, further comprising a spacer moiety between the ELP component and the insulin or functional analog.
 58. The therapeutic agent of claim 57, wherein the spacer moiety comprises one or more of a protease-resistant moiety, a non-peptide chemical moiety, and a protease cleavage site.
 59. The therapeutic agent of claim 58, wherein the protease cleavage site is a thrombin cleavage site, a factor Xa cleavage site, a metalloprotease cleavage site, an enterokinase cleavage site, a Tev cleavage site, or a cathepsin cleavage site.
 60. The therapeutic agent of claim 58, wherein the spacer moiety comprises a non-cleavable moiety having the formula [(Gly)_(n)-Ser]_(m) (SEQ ID NO: 22) where n is from 1 to 4, inclusive, and m is from 1 to 4, inclusive.
 61. The therapeutic agent of any one of claims 52-60, wherein the ELP component comprises at least one repeating unit selected from SEQ ID NOS: 1-12.
 62. The therapeutic agent of claim 61, wherein said repeating unit is VGPXG (SEQ ID NO: 3).
 63. The therapeutic agent of claim 61, wherein the repeating unit is Ile-Pro-Gly-X-Gly (SEQ ID NO: 5) or Leu-Pro-Gly-X-Gly (SEQ ID NO: 7), wherein X is any natural or non-natural amino acid residue, and wherein X varies among at least two units.
 64. The therapeutic agent of claim 62 or 63, wherein each X is independently selected from alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine residues.
 65. The therapeutic agent of any one of claims 52-64, wherein the therapeutic agent has a molecular weight of less than about 50 kDa.
 66. The therapeutic agent of any one of claims 52-65, wherein the ELP component has a Tt greater than 37° C.
 67. The therapeutic agent of any one of claims 52-66, wherein the therapeutic agent is a genetically encoded fusion protein.
 68. A polynucleotide comprising a nucleotide sequence encoding the therapeutic agent of claim
 67. 69. The polynucleotide of claim 68, further comprising an expression control element operably linked to said nucleotide sequence.
 70. The polynucleotide of claim 69, wherein said expression control element comprises a promoter.
 71. A vector comprising the polynucleotide of any one of claims 68-70.
 72. An isolated host cell containing the vector of claim 71 or the polynucleotide of any one of claims 68-70.
 73. A pharmaceutical composition comprising the therapeutic agent of any one of claims 52-67, and a pharmaceutically acceptable carrier and/or excipient.
 74. A method of preventing or treating a biological condition, disorder, or disease in a subject, comprising administering an effective amount of the therapeutic agent of any one of claims 52-67 or the pharmaceutical composition of claim 73 to a subject in need thereof.
 75. The method of claim 74, wherein the subject has diabetes.
 76. A therapeutic agent comprising an elastin-like peptide (ELP) component and a Factor VII/VIIa or functional analog thereof.
 77. The therapeutic agent of claim 76, wherein the ELP component is covalently bonded to the Factor VII/VIIa or functional analog at an N- and/or C-terminus of the Factor VII/VIIa.
 78. The therapeutic agent of claim 76 or 77, wherein a first Factor VII/VIIa or functional analog is covalently bonded to the ELP at the N-terminus of the ELP component, and a second Factor VII/VIIa or functional analog is covalently bonded to the ELP component at the C-terminus of the ELP component.
 79. The therapeutic agent of claim 76, wherein the Factor VII/VIIa or functional analog is covalently bonded to the ELP component at an N- and/or C-terminus of the ELP component.
 80. The therapeutic agent of claim 76 or 77, wherein a first ELP component is covalently bonded to the Factor VII/VIIa or functional analog at an N-terminus thereof, and a second ELP component is covalently bonded to the Factor VII/VIIa or functional analog at a C-terminus thereof.
 81. The therapeutic agent of any one of claims 76-80, further comprising a spacer moiety between the ELP component and factor VII/VIIa or functional analog.
 82. The therapeutic agent of claim 81, wherein the spacer moiety comprises one or more of a protease-resistant moiety, a non-peptide chemical moiety, and a protease cleavage site.
 83. The therapeutic agent of claim 82, wherein the protease cleavage site is a thrombin cleavage site, a factor Xa cleavage site, a metalloprotease cleavage site, an enterokinase cleavage site, a Tev cleavage site, and a cathepsin cleavage site.
 84. The therapeutic agent of claim 82, wherein the spacer moiety comprises a non-cleavable moiety having the formula [(Gly)_(n)-Ser]_(m) (SEQ ID NO: 22) where n is from 1 to 4, inclusive, and m is from 1 to 4, inclusive.
 85. The therapeutic agent of any one of claims 76-84, wherein the ELP component comprises at least one repeating unit selected from SEQ ID NOS: 1-12.
 86. The therapeutic agent of claim 85, wherein said repeating unit is VPGXG (SEQ ID NO: 3).
 87. The therapeutic agent of claim 86, wherein X is any natural or non-natural amino acid residue, and wherein X varies among at least two units.
 88. The therapeutic agent of claim 86, wherein each X is independently selected from alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine residues.
 89. The therapeutic agent of any one of claims 76-88, wherein the therapeutic agent has a molecular weight of less than about 70 kDa.
 90. The therapeutic agent of any one of claims 76-89, wherein the ELP component has a Tt greater than 37° C.
 91. The therapeutic agent of any one of claims 76-90, wherein the therapeutic agent is a genetically encoded fusion protein.
 92. A polynucleotide comprising a nucleotide sequence encoding the therapeutic agent of claim
 91. 93. The polynucleotide of claim 92, further comprising an expression control element operably linked to said nucleotide sequence.
 94. The polynucleotide of claim 93, wherein said expression control element comprises a promoter.
 95. A vector comprising the polynucleotide of any one of claims 92-94.
 96. An isolated host cell containing the vector of claim 95 or the polynucleotide of any one of claims 92-95.
 97. A pharmaceutical composition comprising the therapeutic agent of any one of claims 76-91, and a pharmaceutically acceptable carrier and/or excipient.
 98. A method of preventing or treating a subject for a biological condition, disorder, or disease, comprising administering an effective amount of the therapeutic agent of any one of claims 76-91 or the pharmaceutical composition of claim 97 to a subject in need thereof.
 99. The method of claim 98, wherein the subject has a hemorrhage.
 100. The method of claim 98 or 99, wherein the subject has hemophilia. 